WO2023036957A1 - Use of faecalibacterium to treat a respiratory viral infection - Google Patents
Use of faecalibacterium to treat a respiratory viral infection Download PDFInfo
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- WO2023036957A1 WO2023036957A1 PCT/EP2022/075158 EP2022075158W WO2023036957A1 WO 2023036957 A1 WO2023036957 A1 WO 2023036957A1 EP 2022075158 W EP2022075158 W EP 2022075158W WO 2023036957 A1 WO2023036957 A1 WO 2023036957A1
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- bacteria
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- Respiratory viruses include many viruses which infect cells of the respiratory tract, which cause respiratory disease symptoms and which are transmitted primarily through the respiratory secretions of infected individuals. Respiratory viruses are the most frequent causative agents that cause pathologies in humans and animals. In humans and animals, respiratory virus infections have a global impact on morbidity and mortality. Thus, a plurality of respiratory viruses commonly circulate among men of all ages with high efficiency of human-to-human transmission.
- viruses human respiratory syncytial virus (HRSV), (ii) human parainfluenza virus (HPIV), (iii) human respiratory virus (HRV), (iv) Aleutian disease (ADV), (v) human coronavirus (HCoV), (vi) severe acute respiratory syndrome coronavirus (SARS-CoV 1 and 2), (vii) human metapneumovirus (HPMV), (viii) human bocavirus (HBoV) or (ix) influenza virus (IAV) (Boncristiani et al., 2009, Encyclopedia of microbiology: 500-518; doi: 10.1016/B978-01237944-5.00314-X).
- the gut microbiota in the homeostasis of the immune system, which encompasses the immune response against viruses, including including against respiratory viruses.
- viruses including including against respiratory viruses.
- the gut microbiota affects pulmonary immunity due to an established dialogue between the gut microbiota and the gut and lungs, which is sometimes referred to as the gut-lung axis.
- This gut-lung axis which is bidirectional, encompasses the passage of endotoxins, metabolites and hormones in the circulating blood, and connects the intestinal niche to the lungs.
- the gut microbiota can be significantly altered during a variety of respiratory disorders caused by a wide range of airborne pathogens, particularly pathogenic viruses (Dumas et al., 2018, Cell Microbiol, 20 :e12966).
- pathogenic viruses Dumas et al., 2018, Cell Microbiol, 20 :e12966.
- a reduction in the diversity of the intestinal microbiota has been shown in subjects infected with various respiratory viruses, this reduction in the diversity of the microbiota being associated with increased mortality.
- This increased mortality observed in respiratory virus infections has been associated with a failure of the immune response characterized by the increased production of interferon gamma, IL-6 and CCL2, and by a reduced number of Treg cells in intestine and lungs (Grayson et al., 2018, Front Immunol, Vol. 9: 1587).
- mice models of influenza virus and respiratory syncitial virus altered the diversity of the gut microbiota, with a decrease in the abundance of Firmicutes phyla (Rangelova et al., 2019, Ann Surg doi:10.1097 SLA.0000000000003301 [Epub ahead of print]; Zhang et al., 2020, Frontiers in Microbiology, Vol. 11: Art. 301:1-14). It was observed by He et al. (2002, Canad J Infect Dis, Vol. 2021: 1-10) a low abundance of F. prausnitzii, particularly in people infected with the COVID 19 virus. These authors believe that F.
- prausnitzii would have a potential ability to reduce inflammation and to prevent the occurrence of gastrointestinal co-morbidities, particularly in patients infected with the COVID-19 virus. These authors report the existence of studies which would have shown a correlation between a low abundance of F. prausnitzii and an increased incidence of metabolic inflammatory diseases. It is thus proposed that the anti-inflammatory effects of F. prausnitzii could lead to the prevention and alleviation of symptoms caused by infection with the COVID-19 virus, at least in combination with medicinal agents.
- Patent documents US 2018/0264053 and US 2021/0077541 propose compositions comprising various combinations of bacteria for the purpose of preventing or treating inflammatory diseases.
- the PCT application published under the number WO 2021/146523 describes solid dosage forms allowing an improved oral release of bacteria and agents of bacterial origin, which can be used in particular, because of their anti-inflammatory properties, in the treatment of viral infections.
- Various mechanisms having the effect of reducing an immune response are common to the various respiratory viruses, which includes viruses inducing severe acute respiratory distress syndrome (such as the MERS-CoV and SARS-CoVs viruses) or even other RNA viruses such as respiratory syncitial virus (RSV), parainfuenza virus 3 (HIPV3) and Influenza virus (IAV) (Blanco-Melo et al., 2020, Cell, Vol. 181: 1036-1045).
- severe acute respiratory distress syndrome such as the MERS-CoV and SARS-CoVs viruses
- RSV respiratory syncitial virus
- HIPV3 parainfuenza virus 3
- IAV Influenza virus
- Preventive treatments against infection by various respiratory viruses are known, mainly in the form of vaccines. Given the rate of hospitalizations due to infection by respiratory viruses, and also the large number of deaths found in subjects infected by these viruses, there is a need for the identification of therapeutic treatments, alternative or improved compared to treatments known therapies. Moreover, there does not currently seem to be any effective therapeutic treatment against some of these respiratory viruses, in particular for the treatment of an infection by a SARS-CoV-2 virus. Also, as with the influenza virus, antiviral agents must be administered soon after infection to be effective. This constraint makes it difficult to identify suitable molecules. Many trials have aimed to identify, among the many known antiviral agents, active agents against SARS-CoV-2, but without success until today.
- certain agents have been used for the purpose of reducing certain deleterious physiological consequences of an infection by the SARS-CoV-2 virus, such as (i ) dexamethasone, for the purpose of modulating lung damage due to inflammation and thus reduce the progression of respiratory distress syndrome and the occurrence of death, (ii) immunosuppressive antibodies such as tocilizumab or sarimumab, or even (iii) kinase inhibitors, for the purpose of controlling downstream inflammation.
- dexamethasone for the purpose of modulating lung damage due to inflammation and thus reduce the progression of respiratory distress syndrome and the occurrence of death
- immunosuppressive antibodies such as tocilizumab or sarimumab
- kinase inhibitors for the purpose of controlling downstream inflammation.
- This disclosure relates to bacteria of the genus Faecalibacterium, which includes bacteria of the species Faecalibacterium prausnitzii and Faecalibacterium duncaniae, for their use for the prevention or treatment of an infection of a subject, whether human or animal, by a respiratory virus, preferably by a human respiratory virus.
- the present description relates to bacteria chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae for their use for the prevention or treatment of an infection of a subject, that he either human or animal, by a respiratory virus preferably by a human respiratory virus.
- these bacteria of the genus Faecalibacterium are useful for the prevention or treatment of infection of a subject by a respiratory virus causing severe acute respiratory distress syndrome, which includes infection by a respiratory virus of human preference.
- said bacteria of the genus Faecalibacterium belong to strain A2-165.
- said bacteria of the Faecalibacterium genus belong to strain I-4574, deposited at the CNCM (National Collection of Microorganism Cultures) on December 7, 2011 by INRA (National Institute for Agronomic Research), which has since been called INRAE (National Research Institute for Agriculture, Food and the Environment).
- said respiratory virus is chosen from (i) a human respiratory syncitial virus (HRSV), (ii) a human parainfluenza virus (HPIV), (iii) a human rhinovirus (HRV), (iv) a virus Aleutian disease (ADV), (v) human coronavirus (HCoV), (vi) human metapneumovirus (HPMV), (vii) human bocavirus (HBoV), (viii) human parainfluenza virus (HIPV) (ix ) human influenza virus (IAV), (x) rotaviruses, (xi) caliciviruses, (xii) toroviruses, (xiii) adenoviruses, (xiv) BHV and ADV herpesviruses and (xv) pestiviruses .
- HRSV human respiratory syncitial virus
- HPIV human parainfluenza virus
- HPIV human rhinovirus
- ADV virus Aleutian disease
- HCV human
- said virus is a SARS-CoV respiratory virus, preferably a SARS-CoV-2 respiratory virus.
- said virus is a human influenza virus (IAV).
- these bacteria of the genus Faecalibacterium are useful for reducing the subject's viral load of said respiratory virus, preferably the subject's lung load of said respiratory virus.
- said bacteria, said bacteria of the Faecalibacterium genus are included in a composition, in association with at least one physiologically acceptable excipient.
- said Faecalibacterium bacteria are included in a composition in a form suitable for nasal, oral or rectal administration.
- said oral composition is selected from the group consisting of a food product, a beverage, a pharmaceutical product, a nutraceutical, a food additive, a food supplement and a dairy product.
- said bacteria of the genus Faecalibacterium are included in a composition in a form suitable for administration of 10 3 to 10 11 colony forming units.
- Figure 1 represents the viral load of SARS-CoV-2 virus in hamsters, four days after infection. On the ordinate, the viral load expressed as the number of copies of the SARS-CoV-2 virus genome per ⁇ L.
- Figure 2 represents the viral load of SARS-CoV-2 virus in hamsters, four days after infection. On the ordinate, the viral load expressed as the number of SARS-CoV-2 virus particles per mL. On the abscissa, the groups of animals, from right to left (i) control animals infected with SARS-CoV-2 not treated with F. prausnitzii and (ii) animals infected with SARS-CoV-2 and treated with F. prausnitzii. The difference is statistically significant with a P value of 0.01.
- Figure 3 represents the weight loss induced by viral infection by IAV in 8-week-old male C57BL/6J mice, either in kinetics after infection (Fig. 3A) or at D7 post-infection (Fig. 3B) .
- the results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F. prausnitzii according to the invention (group IAV F. prausnitzii A2.165).
- Figure 3A Abscissa: days.
- Y-axis % of the initial weight of the mice.
- FIG. 4 represents the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 4A) or logarithmic (Fig. 4B) value. The results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F.
- FIG. 4A Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2.165 group.
- Y-axis Copy number of IAV (M1 gene).
- Figure 4B Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2.165 group.
- Y-axis Number of copies of IAV (M1 gene) in Log 10 . ***: p ⁇ 0.001; ****: p ⁇ 0.0001 FIG.
- FIG. 6 represents the expression of genes coding for Interferon beta (Ifnb - Figure 6A) and genes induced by interferon gamma (Mx1 and Isg15 - respectively Figures 6B and 6C), genes linked to viral infection, assessed by qRT-PCR. The same groups as previously indicated are represented. Abscissa for Figures 6A, 6B and 6C: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2-165 group. Ordinate for 6A: Relative expression in Ifnb.
- Ordered for 6B Relative expression in Mx1.
- Ordered for 6C Relative expression in Isg15.
- Figure 7 shows the expression of pro-inflammatory genes encoding two chemokines involved in the recruitment of inflammatory cells: MCP1/CCL2 ( Figure 7A) and CXCL2 ( Figure 7B), assessed by qRT-PCR. The same groups as previously indicated are represented. Abscissa for Figures 7A and 7B: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2-165 group. Ordered for 7A: Relative expression in Mcp1/Ccl2. Ordered for 7B: Relative expression in Cxcl2.
- Figure 8 represents the weight loss induced by viral infection by IAV in 8-week-old male C57BL/6J mice, either in kinetics after infection (Fig. 8A) or at D7 post-infection (Fig. 8B) .
- the results obtained in four groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group), a group infected with IAV and having received a treatment of live F. prausnitzii A2-165 according to the invention (live IAV F. prausnitzii A2-165 group) and a group infected with IAV and having received a treatment of inactivated (pasteurized) F.
- FIG. 9 represents the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig.
- Figure 9A Abscissa: from left to right: Uninfected group, IAV infected group, live IAV F. prausnitzii A2.165 group and pasteurized IAV F. prausnitzii A2.165 group.
- Y-axis Copy number of IAV (M1 gene).
- Figure 9B Abscissa: from left to right: Uninfected group, IAV infected group, live IAV F. prausnitzii A2.165 group and pasteurized IAV F. prausnitzii A2.165 group.
- Y-axis Number of copies of IAV (M1 gene) in Log 10 .
- Figure 10 represents the weight loss induced by viral infection by IAV in 8-week-old male C57BL/6J mice, either in kinetics after infection (Fig. 10A) or at D7 post-infection (Fig. 10B) .
- the results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F. prausnitzii I-4574 according to the invention (group IAV F. prausnitzii I-4574).
- Figure 10A Abscissa: days post infection.
- Y-axis % of the initial weight of the mice.
- Figure 12 represents the expression of the genes coding for Interferon gamma (Ifng - Figure 12A) and Interferon beta (Ifnb - Figure 12B) and of the gene induced by interferon gamma (Isg15 Figures 12C), gene linked to viral infection, assessed by qRT-PCR.
- Abscissa for Figures 12A, 12B and 12C from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii I-4574 group.
- Ordered for 12A Relative expression in Ifng.
- Ordered for 12B Relative expression in Ifnb.
- Ordered for 12C Relative expression in Isg15.
- Figure 13 shows the expression of pro-inflammatory genes: Il6 (Figure 13A), MCP1/CCL2 ( Figure 13B) and CXCL2 (Figure 13C), assessed by qRT-PCR.
- Il6 Figure 13A
- MCP1/CCL2 Figure 13B
- CXCL2 Figure 13C
- Abscissa for Figures 13A, 13B and 13C from left to right: Uninfected group, IAV infected group and IAV F group. prausnitzii I-4574.
- Ordered for 13A Relative expression in Mcp1/Ccl2.
- Ordered for 13B Relative expression in Mcp1/Ccl2.
- Ordered for 13C Relative expression in Cxcl2.
- the inventors have shown that the supply of bacteria of the genus Faecalibacterium, in particular bacteria of the species Faecalibacterium prausnitzii (also called F. prausnitzii in the present description) to subjects infected with a respiratory virus, in particular subjects infected with a SARS-CoV-2 virus and in subjects infected with the influenza virus, causes a very significant reduction in the viral load of the subject, in particular a very significant reduction in the pulmonary viral load of the subject.
- an intake of bacteria of the genus Faecalibacterium in particular of bacteria of the species F.
- prausnitzii prior to infection by a respiratory virus, in particular prior to infection by a SARS-CoV- 2, allows a reduced viral load of the subject who is subsequently infected, in particular allows a reduced pulmonary viral load of the subject who is subsequently infected, in comparison with a subject infected under the same conditions with said respiratory virus but who has not received said contribution of bacteria of the genus Faecalibacterium.
- the reduced viral load that is observed is illustrated both (i) by a decrease in the number of copies of the viral genome and (ii) by a decrease in the number of viral particles, particularly in the lungs.
- the inventors have also shown that the supply of bacteria of the genus Faecalibacterium, in particular bacteria of the species F.
- prausnitzii makes it possible to reduce, in a subject, the presence or the extent of pulmonary lesions caused by an infection of the subject by a respiratory virus, such as SARS-CoV-2 or Influenza. It is also shown in the examples that the supply of bacteria of the genus Faecalibacterium, in particular bacteria of the species F. prausnitzii, makes it possible to reduce, in a subject, the vascular inflammation caused by an infection of the subject by a virus respiratory, such as SARS-CoV-2 or Influenza. The inventors have also shown that the intake of bacteria of the genus Faecalibacterium, in particular bacteria of the species F.
- prausnitzii especially in subjects infected with a respiratory virus such as SARS-CoV-2 or Influenza, induces an increase in level of expression of genes involved in the anti-viral response of the host, such as the following genes: (i) the Ifng gene encoding interferon gamma, (ii) the Ifnb gene encoding interferon beta, (iii) the IfnI3 gene encoding interferon lambda 3, (iv) the Mx1 gene encoding the Mx1 protein binding to GTP and which is induced by interferon, (v) the Isg15 gene which is stimulated by interferon or (vi) the STAT1 gene which is activated by type 1 interferons.
- genes involved in the anti-viral response of the host such as the following genes: (i) the Ifng gene encoding interferon gamma, (ii) the Ifnb gene encoding interferon beta, (iii) the IfnI3 gene encoding interferon
- the present invention relates to bacteria of the genus Faecalibacterium for their use in the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human.
- the bacteria of the genus Faecalibacterium can be chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae.
- the present invention relates to bacteria of the genus Faecalibacterium for their use, as an antiviral agent, for the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus preferably human.
- the bacteria of the genus Faecalibacterium can be chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae. It relates to the use of bacteria of the genus Faecalibacterium for the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human.
- bacteria of the genus Faecalibacterium for the prevention or treatment, as an antiviral agent, of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus preferably human. It relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human . It relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for the prevention or treatment, as an antiviral agent, of an infection of a subject by a respiratory virus, which includes a infection with a respiratory virus, preferably human.
- It relates to a method for preventing or treating an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human, comprising a step during which it is brought to the subject bacteria of the genus Faecalibacterium. It relates to a method for preventing or treating an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human, comprising a step during which it is brought to the subject bacteria of the genus Faecalibacterium in as an antiviral agent.
- the present invention relates to bacteria of the genus Faecalibacterium for reducing damage to the body, in particular for reducing lung damage, caused by infection of a subject with a respiratory virus, which preferably includes infection with a respiratory virus human.
- bacteria of the genus Faecalibacterium for reducing the lesions of the organism, in particular for reducing the pulmonary lesions, caused by an infection of a subject by a respiratory virus, which includes an infection by a virus preferably human respiratory. It relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for reducing the lesions of the organism, in particular for reducing the lesions of the lungs, caused by an infection of a subject by a respiratory virus, this which includes infection with a respiratory virus, preferably human.
- a respiratory virus which includes an infection by a respiratory virus, preferably human, comprising a step during which it is brought about bacteria of the genus Faecalibacterium.
- prevention or treatment of "an infection of a subject” by a respiratory virus is meant according to the present description a prophylactic or therapeutic effect on the level of infection by a respiratory virus when the infection occurs, And more particularly a prophylactic or therapeutic effect on the level of viral load of the subject, after the occurrence of an infection by a virus, here a respiratory virus.
- subject is meant a subject chosen from among humans and animals.
- Animals include non-human mammals that belong to the group of production, livestock or companion animals, such as a canid, a felid or an equine. Most preferably, a subject is a human being.
- human virus is meant a virus having the capacity to infect a human subject.
- non-human virus is meant a virus having the capacity to infect a non-human subject, that is to say an animal. It is specified that some of the viruses of interest for the present description are both human viruses and non-human viruses, such as for example MERS-CoV.
- antiviral agent an agent capable of reducing the viral load of a subject, which includes that the antiviral agent is capable of (i) reducing the number of copies of the viral genome and/or (ii) reducing the number of viral particles in the infected subject's body, which includes in the infected subject's lung tissue.
- F. prausnitzii is a major member of the phylum Firmicutes and is among the most abundant commensal bacteria in the microbiota of the healthy human large intestine.
- prausnitzii is, in particular, known to be one of the most abundant butyrate-producing bacteria in the human digestive tract, the short-chain fatty acid butyrate being very important in the physiology of the intestine, systemic functions and beneficial effects on human health (Macfarlane and Macfarlane (2011), J. Clin. Gastroenterol. 45 Suppl: S120-7).
- changes in the classification of bacteria of the genus Faecalibacterium have been proposed, the proposed new classification being based on the characteristics of the bacterial genome (Sakamoto et al., 2022, International Journal of Systematic and Evolutionary Microbiology, Vol. 72: 005379 – Doi: 10.1099//jsem.0.005379).
- the bacterium Faecalibacterium prausnitzii A2-165 be classified as Faecalibacterium duncaniae.
- the bacteria F. prausnitzii include the bacteria which were classified as belonging to the species F. prausnitzii on the date of September 10, 2021.
- the bacteria of the genus Faecalibacterium in particular the bacteria of the species F prausnitzii, include those referenced in the PCT application published under the number WO 2016/075294, which includes the bacteria deposited according to the Budapest Treaty in the Microorganism Cultures Collection of the Institut Pasteur under the accession numbers I- 4542, I-4544, I-4540, I-4574, I-4543, I-4575, I-4573, I-4644 and I-4546.
- Bacteria of the genus Faecalibacterium, in particular bacteria of the species F prausnitzii also include strains deposited with the American Type Culture Collection (ATCC) under ATCC accession number 27768.
- ATCC American Type Culture Collection
- Bacteria of the genus Faecalibacterium may be bacteria of the A2-165 strain deposited at the German Collection for Cell Cultures and Microorganisms (DMSZ) under the accession number DSM 17677.
- the bacteria of the genus Faecalibacterium can be live bacteria, inactivated bacteria or dead bacteria.
- the bacteria of the genus Faecalibacterium are live bacteria.
- live bacteria is meant according to the present description, bacteria capable of multiplying, under appropriate conditions.
- the bacteria of the genus Faecalibacterium are inactivated bacteria or dead bacteria. According to the present description, "inactivated" bacteria are not capable, at least transiently, which includes permanently, of forming colonies in culture, under appropriate culture conditions.
- inactivated bacteria are bacteria which are no longer, permanently and definitively, capable of forming colonies in culture, under appropriate culture conditions.
- Inactivated bacteria or dead bacteria may have intact or at least partially ruptured membrane walls.
- Inactivated bacteria can be prepared by exposing the bacterial cells to irradiation, for example by ionizing radiation, by inactivation heat, by acid or base inactivation, by inactivation by exposure to air or oxygen, or by freeze-drying. Each of these methods of inactivating bacteria is well known to those skilled in the art. Inactivation by irradiation can be carried out by exposing the bacteria to gamma radiation, to X-rays, or even by exposure to UV radiation.
- Bacteria inactivated by freeze-drying can be reactivated and recultured.
- Thermal inactivation can be carried out by incubating bacteria of the genus Faecalibacterium for a prolonged period, for example at least two hours, at 170° C.
- Thermal inactivation can also be carried out by autoclaving, by subjecting the bacteria of the genus Faecalibacterium to a temperature of 121°C for a period of at least 20 minutes and at an atmospheric pressure of 2 bar.
- thermal inactivation processes such as pasteurization or tyndallization.
- heat inactivation can be achieved by subjecting bacteria of the genus Faecalibacterium to freezing temperature for an extended period of time.
- Inactivation by pH can be achieved by incubating bacteria of the genus Faecalibacterium for an extended period of time in low or high pH, for example for 30 min at pH 2.
- Inactivation by exposure to air can be achieved because bacteria of the genus Faecalibacterium, in particular Faecalibacterium prausnitzii, are extremely oxygen-sensitive (EOS) organisms.
- EOS extremely oxygen-sensitive
- the present description also encompasses not only the use of bacteria of the genus Faecalibacterium, but also the use of a bacterial extract or a bacterial lysate obtained from bacteria of the genus Faecalibacterium, for each of the uses of bacteria of the genus Faecalibacterium which is described in this description.
- An extract or lysate which is suitable for the uses specified in the present description can be prepared from the bacteria of the genus Faecalibacterium, at the end of the growth phase.
- a bacterial strain which is suitable for a use specified in this description can be used in the form of a lysate.
- a "lysate” commonly designates a material obtained after destruction or dissolution of biological cells by a phenomenon known as cell lysis, thus giving rise to the release of the intracellular biological constituents naturally contained in the cells of the bacterium under consideration.
- the term “lysate” is used without preference to designate the entire lysate obtained by lysis of the bacterium under consideration or only a fraction thereof. The lysate used is therefore totally or partially formed of the intracellular biological constituents and of the constituents of the cell walls and membranes of the bacteria.
- the term “fraction” designates more particularly fragments of said bacterium.
- a lysate according to the present description can be the whole lysate obtained by lysis of the bacterial strains considered. This cell lysis can be carried out by various known techniques, such as osmotic shock, thermal shock, by exposure to ultrasound, or alternatively under mechanical stress of the centrifugation type.
- a lysate according to the present description can be obtained by ultrasonic disintegration of a medium comprising bacteria of the genus Faecalibacterium, in particular bacteria of the species F. pausnitzii or of the species F. duncaniae, in suspension in order to to release cytoplasmic fractions, cell wall fragments and metabolic products.
- the respiratory viruses are preferably chosen from respiratory viruses causing severe acute respiratory distress syndrome.
- Respiratory viruses include (i) respiratory viruses infecting human subjects and (ii) respiratory viruses infecting non-human subjects, i.e. animals and more especially non-human mammals, such as for example, without being limiting, cattle, sheep, pigs, canines, felines or even horses.
- the respiratory viruses can be chosen, by way of non-limiting examples, from (i) a human respiratory syncytial virus (HRSV), (ii) a human parainfluenza virus (HPIV), (iii) human rhinovirus (HRV), (iv) Aleutian disease virus (ADV), (v) human coronavirus (HcoV), (vi) human metapneumovirus (HPMV), (vii) human bocavirus (HboV), (viii) human parainfluenza virus (HIPV), (ix) human influenza virus (IAV), (x) rotaviruses, (xi) caliciviruses, (xii) toroviruses, (xiii) adenoviruses, ( xiv) BHV and ADV herpesviruses and (xv) pestiviruses.
- HRSV human respiratory syncytial virus
- HPIV human parainfluenza virus
- HPIV human rhinovirus
- ADV Aleu
- the rotaviruses can be chosen from the RVA, RGB, RVC and RVH viruses.
- the calicivirus can be chosen from novoviruses and sapoviruses.
- the pestiviruses can be chosen from the BVDV and CSFV viruses.
- the coronaviruses are selected from (i) coronaviruses infecting human subjects and (ii) coronaviruses infecting non-human subjects, which includes non-human mammals. Those skilled in the art can refer in particular to the review article by Khbou et al. (2021, Vet Med Sci, Vol. 7: 322-347).
- the coronaviruses infecting non-human subjects can be chosen, by way of non-limiting examples, from (i) bovine coronaviruses, such as bovine coronavirus (BcoV), (ii) coroonaviruses infecting buffaloes, such as Bubaline coronavirus (BuCoV), (iii) coronaviruses infecting camels, such as Middle East respiratory syndrome coronavirus (MERS-CoV), (iv) coronaviruses infecting horses, such as Equine coronavirus (EcoV), (v) coronaviruses infecting rabbits, such as Rabbit coronavirus (RbCoV), (vi) coronaviruses infecting porcines, such as Porcine hemagglutinating encephalomyelitis virus (PHEV), Transmissible gastroenteritis virus (TGEV), Porcine respiratory coronavirus (PRCV), Swine acute diarrhoea syndrome coronavirus (SA
- the human coronaviruses are chosen in particular from (i) a Middle East respiratory syndrome coronavirus (MERS-CoV), and (ii) a coronavirus responsible for severe acute respiratory syndrome (SARS-CoV).
- the SARS-CoV respiratory viruses can be chosen from SARS-CoV-1 viruses and SARS-CoV-2 viruses. They are preferably SARS-CoV-2 respiratory viruses.
- the respiratory viruses can be chosen from Influenza viruses, preferably a human Influenza virus.
- the Influenza virus can be a virus of one of the types A, B or C and is preferentially a type A Influenza virus (also called “IAV” in the present description). It may be an Influenza virus of type A, of a subtype chosen from A(H1N1) and A(H3N2).
- the species of respiratory viruses preferably the species of human respiratory viruses, encompass the different strains, sometimes referred to as “variants”, of said viruses.
- the viruses of the SARS-CoV-2 type encompass the different strains, sometimes referred to as “variants”, of these viruses.
- an Influenza virus belonging to a given subtype is classified according to a subclassification in clades (groups), then in subclades (subgroups).
- a type A Influenza virus can be classified in the A(H1N1) subtype, then in the 68.1 clade and finally in the 68.1.A subclade.
- strains of type A Influenza virus can be classified in the A(H3N2) subtype.
- the invention relates to bacteria of the genus Faecalibacterium for their use for the prevention or treatment of an infection of a subject with a respiratory virus, preferably with a human respiratory virus, to reduce the subject's viral load of said respiratory virus during the infection.
- the bacteria of the genus Faecalibacterium can be chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae.
- the invention relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for the prevention or treatment of an infection of a subject by a respiratory virus, preferably by a human respiratory virus, to reduce the burden virus of the subject into said respiratory virus during the infection.
- the invention relates to a method for the prevention or treatment of an infection of a subject by a respiratory virus, to reduce the viral load of the subject during the infection, comprising a step of supplying said subject with bacteria of the genus Faecalibacterium.
- the invention also relates to a prophylactic or therapeutic method for obtaining a reduced viral load in a subject when he is infected with a respiratory virus, said method comprising a step of supplying said subject with bacteria of the genus Faecalibacterium.
- viral load of a subject within the meaning of the present description, is meant a quantity of virus present in a tissue and/or an organ of said subject.
- the subject's viral load consists of a quantity of virus present in the pulmonary tissue and/or in the pulmonary fluid of said subject.
- a quantity of virus can be expressed (i) in number of copies of viral genome or (ii) in number of infectious viral particles.
- the number of viral genome copies can be determined according to a method comprising a step of amplification of the viral RNA, preferably according to the RT-PCR technique, as illustrated in the examples.
- the number of infectious viral particles can be determined using a viral particle titration method comprising a step of infecting cells sensitive to said virus.
- the results can be expressed in TCID50/mL, ie in the quantity of virus necessary to cause the infection of 50% of the susceptible cells.
- the viral load of a subject is reduced when a decrease of at least 5 times, better still of at least 10 times, the reference viral load is measured, compared to a reference value .
- a reduction in the viral load of a subject in a respiratory virus is attested when a reduction of at least 5 times the number of copies of the genome of said virus, better still of at least 10 times the number of copies of the genome of said virus is measured, relative to a reference value.
- a reduction in the viral load of a subject in a respiratory virus is attested when a decrease of at least 5 times the number of particles of said virus, better still at least 10 times the number of particles of said virus, is measured, relative to a reference value.
- a supply of bacteria of the genus Faecalibacterium has the property, in a subject infected with a respiratory virus, in particular infected with a SARS-CoV-2 virus, of reducing the viral load by more than 10 times. , compared with a subject who did not receive a supply of bacteria of the genus Faecalibacterium, whether this viral load is expressed (i) as a number of copies of the viral genome or (ii) as a number of viral particles.
- Compositions The present invention also relates to a composition comprising, in a physiologically acceptable medium, at least bacteria of the genus Faecalibacterium, in particular bacteria of the species F prausnitzii or bacteria of the species F. duncaniae.
- a composition according to the present description has a formulation suitable for its administration intranasally, orally or rectally.
- Suitable Faecalibacterium bacteria are described elsewhere in this specification.
- the chosen strain of Faecalibacterium in particular of F. prausnitzii or of F. duncaniae, is used as the only bacterial strain present in the composition.
- a combination of several strains of Faecalibacterium, in particular of F. prausnitzii or of F. duncaniae are the only bacterial strains present in the composition.
- duncaniae are combined with bacteria from one or more other probiotic bacterial strains, which includes other commensal probiotic bacterial strains.
- probiotics include strains of bacteria belonging to the following genera: Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, and three yeasts Kluyveromyces, Saccharomyces, Candida and combinations thereof.
- the probiotics may be chosen from the group consisting of the following bacterial species: Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei (from now on Lacticaseibacillus casei), Lactobacillus paracasei (from now on Lacticaseibacillus paracasei), Lactobacillus salivarius (now Ligilactobacillus salivarius), Lactobacillus lactis (now Lactobacillus delbrueckii subsp.
- Lactis Lactis
- Lactobacillus rhamnosus now Lacticaseibacillus rhamnosus
- Lactobacillus johnsonii Lactobacillus plantarum (now Lactiplantibacillus plantarum subsp.
- Lactococcus lactis Lactococcus lactis, Enterococcus faecium, Sac cerevisiae, Saccharomyces boulardii or their mixtures, preferably chosen from the group consisting of Bifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longum NCC2705 (CNCM 1-2618), Bifidobacterium longum N CC490 (CNCM 1-2170), Bifidobacterium lactis NCC2818 (CNCM I-3446), Bifidobacterium breve strain A, Lactobacillus paracasei NCC2461 (CNCM 1-2116), Lactobacillus johnsonsii NCC533 (CNCM 1-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CGMCC 1.3724), Enterococcus faecium SF 68 (
- a composition according to the present description is combined, for example in a kit, with one or more other agents useful for the treatment of an infection of a subject by a SARS-CoV-2 virus.
- these embodiments include those in which a composition according to the present description is combined, for example in a kit, with one or more antibodies directed against a SARS-CoV-2 virus.
- these embodiments also encompass those in which a composition according to the present description is combined, for example in a kit, with one or more anti-viral agents.
- the composition also includes one or more prebiotics.
- prebiotic is used in its conventional sense in the state of the art. Prebiotics consist of food substances that promote the growth of probiotic bacteria, including bacteria included in the microbiota.
- Non-limiting examples of prebiotics include: oligosaccharides optionally containing fructose, galactose, mannose; dietary fibers, in particular fermentable fibers, soy fibers; inulin; and their combinations.
- the preferred prebiotics are fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), isomalto-oligosaccharides (IMO), xylo-oligosaccharides (XOS), arabino-xylo-oligosaccharides (AXOS), mannan-oligosaccharides (MOS), soy oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose-oligosaccharides (PAO), malto-oligosaccharides, resistant starches, gums and/or hydrolysates thereof, pectins and/or hydrolysates thereof, or combinations thereof.
- the composition further comprises one or more vitamins.
- the vitamins can be folic acid, vitamin B12 and vitamin B6, especially folic acid, and vitamin B12, especially folic acid.
- the composition includes one or more vitamins that are fat-soluble, for example, one or more of vitamin A, vitamin D, vitamin E, and vitamin K.
- the composition includes a or more polyphenols, such as flavanols, flavanones, flavonols, hydroxycinnamic acids and anthocyanins.
- the composition further includes one or more minerals.
- the minerals can be selected from sodium, potassium, chloride, calcium, phosphate, magnesium, iron, zinc, copper, selenium, manganese, fluorine, iodine, chromium or molybdenum. Minerals are usually added in the form of salt. The minerals can be added alone or in combination.
- a composition according to the present description generally comprises carriers or vehicles.
- Carriers or “vehicles” refer to materials suitable for administration and include any material known in the state of the art, such as, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent or the like, which is non-toxic and which does not interact with the components of the composition in a deleterious manner.
- nutritionally acceptable carriers include, for example, water, saline solutions, alcohols, silicones, waxes, petrolatum, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, oil of perfume, monoglycerides and diglycerides of fatty acids, esters of petroleum fatty acids, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
- the composition further includes any other ingredient or excipient known to be employed in the type of composition in question.
- Non-limiting examples of such ingredients include: proteins, amino acids, carbohydrates, oligosaccharides, lipids, nucleotides, nucleosides, other vitamins, minerals and other micronutrients.
- the composition contains a source of carbohydrates, for example in the form of prebiotics, or prebiotics when they are present in the composition. Any carbohydrate source commonly found in infant formula, such as lactose, sucrose, maltodextrin, starch, and mixtures thereof, may be used, although the preferred carbohydrate source is lactose.
- a composition according to the present description consists of a nutritional composition, for example a nutritional composition whose constitution is adapted to feed a human subject or else a non-human mammalian subject.
- the composition is a nutritional composition for a human subject.
- a composition according to the invention intended for oral administration, can be provided with a coating resistant to gastric juice, in order to ensure that the bacterial strain of the invention comprised in said composition can cross the damaged stomach. Release of the bacterial strain may thus occur for the first time in the upper intestinal tract.
- the nutritional composition is selected from whole food compositions, food supplements, nutraceutical compositions and the like.
- the composition of the present description can be used as a food ingredient and/or food ingredient for human subjects or non-human mammalian subjects.
- the food ingredient can be in the form of a solution or a solid, depending on the use and/or the mode of application and/or the mode of administration.
- the term “food” refers to liquid (i.e. beverages), solid or semi-solid dietary compositions, in particular total food compositions (food replacement) , who does not require no additional supply of nutrients or dietary supplement compositions. Dietary supplement compositions do not completely replace the supply of nutrients by other means.
- the term “food ingredient” encompasses a formulation that is or can be added to functional foods or foodstuffs as a dietary supplement.
- nutritional or “nutraceutical” or “functional” food is meant a food material which contains ingredients having beneficial effects on health or capable of improving physiological functions.
- food supplement is meant a food material intended to supplement a normal diet.
- a food supplement is a concentrated source of nutrients or other substances having a nutritional or physiological effect, when taken alone or in combination in small amounts.
- “functional food” is used to designate food materials and corresponding products to which importance is attributed not only because of their nutritional and taste value but also because of the presence of ingredients having beneficial physiology.
- the composition is a fermented dairy product or milk-based product, which is preferably administered or ingested orally one or more times per day.
- Fermented milk products include milk products, such as (but not limited to) desserts, yoghurts, yoghurt drinks, cottage cheese, kefir, fermented milk drinks, buttermilk , cheeses, salad dressings, low-fat spreads, cream cheese, soy drinks, ice cream, etc.
- the nutritional and/or nutritional supplement compositions may be non-dairy or unfermented dairy products.
- Unfermented dairy products can include ice cream, nutrition bars and seasonings, and others.
- Non-dairy products may include powdered drinks and nutrition bars, etc. Products can be made using known methods, such as adding an effective amount of F. prausnitzii bacteria, or a combination of bacteria including F.
- the composition is a beverage which may be a functional beverage or a therapeutic drink, thirst quencher or conventional drink.
- the composition according to the present description can be used as an ingredient for soft drinks, a fruit juice or a drink comprising whey proteins, teas, cocoa drinks, milk drinks, yoghurts including drinkable yoghurts, cheeses, ice creams, popsicles and desserts, confectionery, cookies, cakes and cake mixes, snacks, healthy foods and beverages, frostings, acidified soy beverage/juice, aseptic/tapped chocolate beverage, bar mixes, powdered beverage mixes, calcium fortified soy milk and chocolate, calcium fortified coffee beverage.
- the composition includes any other ingredient or excipient known to be employed in the type of composition in question.
- Non-limiting examples of such ingredients include: proteins, amino acids, carbohydrates, oligosaccharides, lipids, prebiotics or probiotics, nucleotides, nucleosides, other vitamins, minerals and other micronutrients.
- F. prausnitzii bacteria optionally in combination with probiotic bacteria of one or more other strains, are administered to the subject in the form of a pharmaceutical composition, which composition may consist of a product Live Biotherapeutic product (LBP) type reference: Front Med (Lausanne) Rouanet et al. 2020 Jun 19; 7: 237. Doi: 10.3389/fmed.2020.00237.
- LBP Live Biotherapeutic product
- the bacteria of interest can be combined with pharmaceutically acceptable excipients, and optionally sustained release matrices, such as biodegradable polymers, to form therapeutic compositions.
- pharmaceutically acceptable excipients such as a pharmaceutically acceptable graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, or graft copolymer, or graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft
- the active ingredient or the combination of active ingredients active ingredients can be administered in unit dosage form, in mixture with conventional pharmaceutical carriers, to animals and humans.
- suitable unit dosage forms include (i) oral dosage forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, including sublingual and orally, (ii) intranasally such as aerosols and (iii) rectally such as suppositories.
- the pharmaceutical composition must be stable under the conditions of manufacture and storage and must be preserved from the contaminating action of exogenous microorganisms, such as pathogenic bacteria and fungi.
- the term "therapeutically effective amount”, when used, is an equivalent term that refers to the amount of a therapy (e.g., prophylactic or therapeutic agent) that is sufficient to reduce the severity and/or duration of a disease, ameliorate one or more of its symptoms, prevent the progression of a disease or cause regression of a disease, or which is sufficient to result in the prevention of development, recurrence, onset, or progression of a disease or one or more of its symptoms, or to enhance or enhance the prophylactic and/or therapeutic effect(s) of another therapy (e.g., another therapeutic agent) useful for treating a disease.
- a therapy e.g., prophylactic or therapeutic agent
- the F e.g., prophylactic or therapeutic agent
- prausnitzii bacteria are present in an amount sufficient to induce a reduction in the viral load of a respiratory virus in the subject treated, when this subject is infected with said respiratory virus, relative to the expected viral load in a subject who has not received said F. prausnitzii bacteria.
- the bacteria or bacteria, in particular F. prausnitzii bacteria can be in various forms, for example in liquid form or in powder form.
- the bacteria or bacteria, in particular the F. prausnitzii bacteria can be in freeze-dried form.
- duncaniae which is supplied to the subject may be variable, depending on the physiological state of said subject, and in particular depending on whether the bacteria are administered for a prophylactic purpose or in a therapeutic purpose.
- the quantity of F. prausnitzii bacteria which must be provided to said subject can easily be adapted by those skilled in the art.
- the composition comprises an amount of bacteria of the genus Faecalibacterium which is suitable for daily intake, preferably daily oral intake, of at least 10 7 colony forming units (or "CFU" for "Colony Forming Units").
- the daily intake, in particular the daily oral intake, of bacteria of the genus Faecalibacterium is at most 10 11 colony forming units (or “CFU” for “Colony Forming Units”).
- the composition comprises an amount of bacteria of the Faecalibacterium genus ranging from 10 7 colony-forming units to 10 11 colony-forming units.
- the amount of such probiotic bacteria is determined by one skilled in the art based on his general knowledge. The amount of these other probiotic bacteria can vary from 10 3 to 10 13 other probiotic bacteria.
- a composition according to the present description generally comprises carriers or vehicles.
- Carriers or “vehicles” refer to materials suitable for administration and include any material known in the state of the art, such as, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent or the like, which is non-toxic and which does not interact with the components of the composition in a deleterious manner.
- nutritionally acceptable carriers include, for example, water, saline solutions, alcohols, silicones, waxes, petrolatum, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, oil of perfume, monoglycerides and diglycerides of fatty acids, esters of petroleum fatty acids, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
- said composition is in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.
- Such a pharmaceutical composition can be presented in the form of a package comprising a plurality of dosage units.
- dosage unit is used in its conventional sense in pharmacy (eg one pill, one capsule, one tablet, the contents of one ampoule, etc.).
- Uses This description relates to the prophylactic uses and the therapeutic uses of a composition as defined in the present application, against an infection of a subject by a respiratory virus, in particular against a infection of a human subject by a respiratory virus.
- the compositional characteristics, including of a prophylactic composition and a therapeutic composition, including in various embodiments, are described in detail in this description, which includes the amounts of active ingredient(s). ), especially the quantities of bacteria of the genus Faecalibacterium, in particular of bacteria of the species F.
- a prophylactic composition and a therapeutic composition according to the present description may have a qualitative and quantitative constitution in active ingredients and in excipient(s) which is identical, the only distinction being that the "prophylactic" composition is administered, as a preventive measure, to a subject not infected with a respiratory virus, whereas the same composition, this time qualified as “therapeutic”, is administered to a subject who is infected with a respiratory virus.
- a composition in accordance with the present description optionally in the form of a dietary supplement composition, is formulated for daily administration, for example for daily administration in one or two doses, for example at meal times.
- a composition according to the present description in particular a prophylactic composition according to the present description, is administered to the subject chronically, for a long period of time, for example for several months or even for several years.
- a respiratory virus for example by a SARS-CoV-2 virus or else by an Influenza virus, in particular an Influenza virus of type A (IAV).
- IAV Influenza virus of type A
- a composition according to the present description in particular a therapeutic composition according to the present description, is administered to a subject infected with a respiratory virus, (i) until the disappearance of the symptoms caused by the infection with said respiratory virus or (ii) until the presence of said respiratory virus in said subject becomes undetectable
- a respiratory virus in particular a respiratory virus
- the invention is described below in more detail by means of the following examples which are presented by way of illustration uniquely.
- a first group of hamsters was inoculated with the SARS-CoV-2 virus (UCN1 strain/GISAID identifier EPI_ISL_911513), by intranasal injection of a dose of 10 4 TCID 50 of the virus.
- a second group of hamsters was treated by oral administration of F. prausnitzii at the rate of a daily quantity of F. prausnitzii of 10 9 colony forming units (CFUs), during the 5 days preceding infection with SARS-CoV- 2, then for 4 days following inoculation with the SARS-CoV-2 virus.
- CFUs colony forming units
- the hamsters were inoculated with the SARS-CoV-2 virus (UCN1 strain), by intranasal injection of a dose of 10 4 TCID 50 of the virus, as for the first group.
- the animals of the two groups were sacrificed on D4 following the inoculation of the SARS-CoV-2 virus.
- A.2. Viral load measurement protocols The evaluation of the viral load of the SARS-CoV-2 virus was carried out using lung samples taken from the animals on the day of their sacrifice. Detection of the SARS-CoV-2 viral genome was performed using a real-time PCR method.
- the detection of the SARS-COV-2 viral genome is based on the amplification of the E gene (position 26141-26253) by TaqMan RT-qPCR using a pair of nucleotide primers and a TaqMan probe described by Corman and para. (2020), The following method was carried out: - The viral RNA is extracted from 140 ⁇ L of clarified supernatant of organ tissue homogenate (diluted to 1/ 50th ) (ie lung) or from a volume of 140 ⁇ L of biological fluids (ie oropharyngeal swab diluted in a volume of 500 ⁇ L of DMEM medium containing 1% antibiotics).
- the extraction of the viral RNA is carried out using the commercial kit Qiagen Viral RNA mini kit (Qiagen, France) according to the manufacturer's instructions.
- the following nucleotide primers and the TaqMan probe were used: - E_Sarbeco_F1 ACAGGTACGTTAATAGTTAATAGCGT (SEQ ID NO. 1) - E_Sarbeco_R2 ATATTGCAGCAGTACGCACACA (SEQ ID NO. 2) - E_Sarbeco_P1 ACACTAGCCATCCTTACTGCGCTCG [5']'am [3']BHQ-1 ( SEQ ID NO.3).
- the primer pairs and the TaqMan probe have been described by Corman et al.
- TaqMan RT-qPCR was performed in a total volume of 25 ⁇ L
- TaqMan RT-qPCR assays were performed in a total volume of 25 ⁇ L containing 2.' ⁇ L of extracted RNA, 12.5 ⁇ L of 2x reaction mix, 1 ⁇ L of 225 mM MgCl (Invitrogen), 4.' ⁇ L of RNase-free water, 2 ⁇ L of each of the primers (10 ⁇ M), 0.25 ⁇ L of probe (10 ⁇ M) and 0.25 ⁇ L of enzyme (Quantitect Probe RT-mix).
- the efficiency, the slope and the correlation coefficient (R 2 ) were determined with the Rotor Gene software. All PCR reactions were performed in duplicate.
- the titration of the SARS-CoV-2 viral strain was carried out by infecting cells sensitive to the virus according to the following method: The titration of the infectious viral particles is carried out on 96-well microplates. A suspension of VeroE6 cells, sensitive to the SARS-CoV-2 virus, was prepared in DMEM medium containing 10% fetal bovine serum (FCS) and 1% antibiotics (penicillin/streptomycin/amphotericin B) so as to obtain a final concentration of 1.10 5 cells per ml.
- FCS fetal bovine serum
- antibiotics penicillin/streptomycin/amphotericin B
- This cell suspension was seeded, in each well of the microplate, 24 hours before the inoculation of the samples.
- the microplates were incubated at 37°C in an oven containing 5% CO2. Twenty-four hours later, a first dilution of the sample to 1/10 is carried out in so-called "complete" medium, that is to say DMEM supplemented with fetal calf serum (10%) and a mixture penicillin/streptomycin (1%). Then from this diluted sample, serial dilutions of factor 4 are carried out in complete medium. The microplates containing the cell suspension are taken from the oven.
- FIGS. 1 and 2 show a statistically significant decrease of the viral load in the animals of the second group which was treated with F. prausnitzii, by comparison with the animals of the second group which did not receive F. prausnitzii, that the viral load be evaluated in number of copies of the genome of SARS-CoV-2 or in number of infectious virus particles.
- Example 2 Effect of F. prausnitzii on infection by the influenza virus (IAV H3N2)
- IAV H3N2 influenza virus
- mice received only the excipient (PBS-glycerol 16%) throughout the procedure and was not infected (MOCK control).
- a second group received the excipient (PBS-glycerol 16%) and was inoculated after 5 days of treatment with the IAV virus (H 3 N 2 Strain Scotland/20/74), by intranasal injection of a dose of 50 PFU of virus per mouse.
- mice were infected with the H 3 N 2 virus (Scotland/20/74 strain) by intranasal injection of a dose of 50 PFU of the virus. Treatment with F. prausnitzii was continued for 7 days after infection, until sacrifice. Weight was monitored daily after infection.
- A.2. Protocols for measuring the viral load The evaluation of the viral load of the IAV virus was carried out using lung samples taken from the animals on the day of their sacrifice. The measurement of the number of copies of the genome of the IAV virus was carried out according to the specific qRT-PCR method (Taqman method).
- RNA was extracted from the lungs by grinding in RA1 buffer (Macherey Nagel) containing 1% ⁇ -mercaptoethanol.
- the RNA was retrotranscribed into cDNA by specific reverse transcription using primers recognizing the M1 region of the IAV virus (5 ⁇ -TCT AAC CGA GGT CGA AAC GTA-3 ⁇ - SEQ ID NO. 4).
- primers recognizing the M1 region of the IAV virus (5 ⁇ -TCT AAC CGA GGT CGA AAC GTA-3 ⁇ - SEQ ID NO. 4).
- SuperScript® II reverse transcriptase Invitrogen.
- the PCR is carried out using TaqMan Universal PCR Master Mix (Applied Biosystems) and specific primers for the M1 region of IAV (sense: 5 ⁇ - AAG ACC AAT CCT GTC ACC TCT GA-3 – SEQ ID NO.
- 5 ⁇ anti-sense 5 ⁇ -CAA AGC GTC TAC GCT GCA GTC C-3 ⁇ - SEQ ID NO. 6
- a specific TaqMan probe marked FAM, TAMRA (5 ⁇ -TTT GTG TTC ACG CTC ACC GTG CC-3 ⁇ - SEQ ID NO. 7).
- the amplification was carried out on the Quantstudio 5 (Applied Biosystems). The number of copies was evaluated using a range of plasmids containing the gene of interest.
- A.3 Gene expression measurement protocol The expression of the different genes was carried out from lung samples taken from the animals on the day of their sacrifice. The expression of the genes was carried out according to the method by specific qRT-PCR (Sybergreen method).
- FIG. 3 shows the weight loss induced by viral infection, either in kinetics after infection (Fig. 3A) or at D7 post-infection (Fig. 3B). The infected mice progressively lose weight to reach a significant weight loss compared to the uninfected animals (p ⁇ 0.001). A significant decrease in weight loss (p ⁇ 0.01) is observed in animals treated with F. prausnitzii A2-165, compared to animals which did not receive F. prausnitzii.
- Figure 4 shows the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig.
- FIG. 4A shows the viral load in the infected mice (p ⁇ 0.0001).
- the animals which have been treated with F. prausnitzii A2-165 show a very significant reduction (p ⁇ 0.001) in the viral load compared to the animals which have not received F. prausnitzii.
- FIG. 5C shows the expression of the genes encoding interferon gamma (Ifng) and of the genes induced by interferon gamma (Mx1 and Isg15) evaluated by qRT-PCR. This analysis shows that treatment with F. prausnitzii A2-165 limits the expression of these genes, induced by viral infection, which correlates with the decrease in viral load.
- Figure 7 shows the expression of pro-inflammatory genes encoding two chemokines involved in the recruitment of inflammatory cells (MCP1/CCL2 and CXCL2). This analysis shows that treatment with F. prausnitzii A2-165 limits significantly the expression of these genes, indicating that the treatment limits the inflammation at the pulmonary level.
- FIG. 8 shows the weight loss induced by viral infection, either in kinetics after infection (Fig. 8A) or on D7 post-infection (Fig. 8B). The infected mice progressively lose weight to reach a significant weight loss compared to the uninfected animals (p ⁇ 0.0001). A similar decrease in weight loss is observed in animals treated with live or inactivated F.
- FIG. 9 shows the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 9A) or logarithmic (Fig. 9B) values. As expected, the viral load is significant in the infected mice (p ⁇ 0.0001). Animals which have been treated with live F. prausnitzii strain A2-165 show a significant decrease (p ⁇ 0.01) in viral load compared to animals which have not received F. prausnitzii. A similar decrease is observed with the pasteurized strain A2-165. C3. Impact of the F.
- FIG 11 shows the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 11A) or logarithmic (Fig. 11B) values. As expected, the viral load is significant in infected mice (p ⁇ 0.01). The animals which have been treated with the F. prausnitzii I-4574 strain show a significant decrease (p ⁇ 0.01) in the viral load compared to the animals which have not received F. prausnitzii.
- Figure 12 shows the expression of the genes encoding Interferon gamma (Ifng) and beta (Ifnb) and the gene induced by interferon gamma (Isg15) evaluated by qRT-PCR. This analysis shows that treatment with F.
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Abstract
The present invention relates to bacteria of the genus Faecalibacterium, in particular bacteria of the species F. Prausnitzii or bacteria of the species F. duncaniae, for use in the prevention or treatment of an infection in a subject with a respiratory virus, preferably a human respiratory virus.
Description
Description Titre : Utilisation de Faecalibacterium pour traiter une infection par un virus respiratoire Domaine technique La présente invention se rapporte au domaine du traitement des infections par les virus respiratoires. Technique antérieure Les virus respiratoires englobent de nombreux virus qui infectent les cellules du tractus respiratoire, qui provoquent des symptômes pathologiques respiratoires et qui se transmettent principalement par les sécrétions respiratoires des sujets infectés. Les virus respiratoires sont les agents causals les plus fréquents qui provoquent des pathologies chez l’homme et l’animal. Chez l’homme, et l’animal, les infections par des virus respiratoires ont un impact mondial sur la morbidité et la mortalité. Ainsi, une pluralité de virus respiratoires circule communément chez les hommes de tous âges avec une grande efficacité de transmission d’homme à homme. Il s’agit en particulier des virus suivants : (i) le virus respiratoire syncitial humain (HRSV), (ii) le virus humain parainfluenza (HPIV), (iii) le virus respiratoire humain (HRV), (iv) le virus de la maladie Aléoutienne (ADV), (v) le coronavirus humain (HCoV), (vi) le coronavirus responsable du syndrome respiratoire aigu sévère (SARS-CoV 1 et 2), (vii) le metapneumovirus humain (HPMV), (viii) le bocavirus humain (HBoV) ou encore (ix) le virus de l’influenza (IAV) (Boncristiani et al., 2009, Encyclopedia of microbiology : 500-518 ; doi : 10.1016/B978-01237944-5.00314-X). Concernant la réponse immunitaire à l’encontre d’une infection virale, il existe un faisceau croissant de preuves indiquant le rôle critique du microbiote intestinal dans l’homéostasie du système immunitaire, ce qui englobe la réponse immunitaire à l’encontre des virus, y compris à l’encontre des virus respiratoires. Au sein des communautés microbiennes intestinales, les Bacteroidetes et les Firmicutes sont prédominantes. Les communautés microbiennes prédominantes dans l’intestin et dans les poumons sont similaires. Le microbiote intestinal affecte l’immunité pulmonaire du fait d’un dialogue établi entre le microbiote intestinal et l’intestin et les poumons, qui est parfois désigné comme l’axe intestin-poumons. Cet axe intestin-poumons, qui est bidirectionnel, englobe le
passage d’endotoxines, de métabolites et d’hormones dans le sang circulant, et relie la niche intestinale aux poumons. Il est connu que le microbiote intestinal peut être considérablement modifié au cours d’une variété de troubles respiratoires provoqués par une large gamme de pathogènes transportés par voie aérienne, en particulier par des virus pathogènes (Dumas et al., 2018, Cell Microbiol, 20:e12966). En particulier, il a été montré une réduction dans la diversité du microbiote intestinal chez des sujets infectés par divers virus respiratoires, cette réduction dans la diversité du microbiote étant associée à une mortalité accrue. Cet accroissement de mortalité observée dans les infections par des virus respiratoires a été associée à une défaillance de la réponse immunitaire caractérisée par la production accrue d’interféron gamma, d’IL-6 et de CCL2, et par un nombre réduit de cellules Tregs dans l’intestin et les poumons (Grayson et al., 2018, Front Immunol, Vol. 9 : 1587). De même, des modèles murins du virus de la grippe et du virus respiratoire syncitial (VRS) ont altéré la diversité du microbiote intestinal, avec une diminution de l'abondance des phyla Firmicutes (Rangelova et al., 2019, Ann Surg doi:10.1097SLA.0000000000003301 [Epub ahead of print]; Zhang et al., 2020, Frontiers in Microbiology, Vol. 11 : Art. 301:1-14). Il a été observé par He et al. (2002, Canad J Infect Dis, Vol. 2021 : 1-10) une faible abondance de F. prausnitzii notamment chez des personnes infectées par le virus COVID 19. Ces auteurs estiment que F. prausnitzii aurait une capacité potentielle à réduire l’inflammation microbienne et à prévenir la survenue de co-morbidités gastrointestinales, particulièrement chez des patients infectés par le virus COVID-19. Ces auteurs rapportent l’existence d’études qui auraient montré une corrélation entre une faible abondance de F. prausnitzii et une incidence accrue de maladies inflammatoires métaboliques. Il est ainsi proposé que les effets anti- inflammatoires de F. prausnitzii pourraient conduire à la prévention et au soulagement de symptômes provoqués par une infection par le virus COVID-19, à tout le moins en combinaison avec des agents médicamenteux. Les documents de brevet US 2018/0264053 et US 2021/0077541 proposent des compositions comprenant diverses combinaisons de bactéries aux fins de prévenir ou traiter des maladies inflammatoires. La demande PCT publiée sous le n° WO 2021/146523 décrit des formes de dosage solides permettant une libération orale améliorée de bactéries et d’agents d’origine bactérienne, lesquelles peuvent notamment être utilisées, en raison de leurs propriétés anti-inflammatoires, dans le traitement d’infections virales.
Divers mécanismes ayant pour effet de réduire une réponse immunitaire sont communs aux différents virus respiratoires, ce qui englobe les virus induisant un syndrome de détresse respiratoire sévère aigu (comme les virus MERS-CoV et SARS-CoVs) ou encore d’autres virus à ARN comme le virus respiratoire syncitial (RSV), le virus parainfuenza 3 (HIPV3) et le virus de l’Influenza (IAV) (Blanco-Melo et al., 2020, Cell, Vol. 181 : 1036- 1045). On connait des traitements préventifs à l’encontre d’une infection par divers virus respiratoires, principalement sous la forme de vaccins. Compte tenu du taux des hospitalisations dues à une infection par les virus respiratoires, et également du nombre important de décès retrouvés chez les sujets infectés par ces virus, il existe un besoin pour l’identification de traitements thérapeutiques, alternatifs ou améliorés par rapport aux traitements thérapeutiques connus. De plus, il ne semble pas exister aujourd’hui de traitement thérapeutique efficace contre certains de ces virus respiratoires, en particulier pour le traitement d’une infection par un virus SARS-CoV-2. Également, comme c’est le cas pour le virus de l’influenza, des agents antiviraux doivent être administrés peu de temps après l’infection pour être efficaces. Cette contrainte rend difficile l’identification de molécules appropriées. De nombreux essais ont visé à identifier, parmi les nombreux agents antiviraux connus, des agents actifs contre le SARS-CoV-2, mais sans succès jusqu’à aujourd’hui. Selon d’autres stratégies, en l’absence d’agents actifs directement sur les particules virales, certains agents ont été utilisés aux fins de réduire certaines conséquences physiologiques délétères d’une infection par le virus SARS-CoV-2, telle que (i) la dexaméthasone, aux fins de moduler les atteintes aux poumons dues à une inflammation et ainsi réduire la progression du syndrome de détresse respiratoire et la survenue d’un décès, (ii) des anticorps immunosuppressifs tels que le tocilizumab ou le sarimumab, ou encore (iii) des inhibiteurs de kinase, aux fins de contrôler l’inflammation en aval. Il demeure un besoin pour des traitements prophylactiques ou thérapeutiques des infections par un virus respiratoire, alternatifs ou améliorés par rapport aux traitements connus. Résumé de l’invention La présente description concerne des bactéries du genre Faecalibacterium, ce qui inclut les bactéries des espèces Faecalibacterium prausnitzii et Faecalibacterium
duncaniae, pour leur utilisation pour la prévention ou le traitement d’une infection d’un sujet, qu’il soit humain ou animal, par un virus respiratoire de préférence par un virus respiratoire humain. Ainsi, la présente description concerne des bactéries choisie parmi les bactéries de l’espèce F. prausnitzii et les bactéries de l’espèce F. duncaniae pour leur utilisation pour la prévention ou le traitement d’une infection d’un sujet, qu’il soit humain ou animal, par un virus respiratoire de préférence par un virus respiratoire humain. Dans certains modes de réalisation, ces bactéries du genre Faecalibacterium sont utiles pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire provoquant un syndrome aigu sévère de détresse respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Dans certains modes de réalisation, lesdites bactéries du genre Faecalibacterium appartiennent à la souche A2-165. Dans certains autres modes de réalisation, lesdites bactéries du genre Faecalibacterium appartiennent à la souche I-4574, déposée à la CNCM (Collection Nationale de Cultures de Microorganismes) le 7 décembre 2011 par l’INRA (Institut National de la Recherche Agronomique), qui est depuis dénommé INRAE (Institut National de la Recherche pour l’Agriculture, l’Alimentation et l’Environnement). Dans certains modes de réalisation, ledit virus respiratoire est choisi parmi (i) un virus respiratoire syncitial humain (HRSV), (ii) un virus humain parainfluenza (HPIV), (iii) un rhinovirus humain (HRV), (iv) un virus de la maladie Aléoutienne (ADV), (v) un coronavirus humain (HCoV), (vi) un metapneumovirus humain (HPMV), (vii) un bocavirus humain (HBoV), (viii) un virus parainfluenza humain (HIPV) (ix) un virus de l’influenza humain (IAV), (x) les rotavirus, (xi) les calicivirus, (xii) les torovirus, (xiii) les adenovirus, (xiv) les herpesvirus BHV et ADV et (xv) les pestivirus. Dans certains modes de réalisation, ledit virus est un virus respiratoire SARS- CoV, de préférence un virus respiratoire SARS-CoV-2. Dans certains autres modes de réalisation, ledit virus est un virus de l’influenza humain (IAV). Dans certains modes de réalisation, ces bactéries du genre Faecalibacterium sont utiles pour réduire la charge virale du sujet en ledit virus respiratoire, de préférence la charge pulmonaire du sujet en ledit virus respiratoire.
Dans certains modes de réalisation, lesdites bactéries lesdites bactéries du genre Faecalibacterium sont comprises dans une composition, en association avec au moins un excipient physiologiquement acceptable. Dans certains modes de réalisation, lesdites bactéries du genre Faecalibacterium sont comprises dans une composition sous une forme adaptée pour une administration par voie nasale, orale ou rectale. Dans certains modes de réalisation, ladite composition par voie orale est choisie dans le groupe constitué d’un produit alimentaire, une boisson, un produit pharmaceutique, un nutraceutique, un additif alimentaire, un supplément alimentaire et un produit laitier. Dans certains modes de réalisation, lesdites bactéries du genre Faecalibacterium sont comprises dans une composition sous une forme adaptée pour une administration de 103 à 1011 unités formant des colonies. Brève description des dessins La Figure 1 représente la charge virale en virus SARS-CoV-2 de hamsters, quatre jours après l’infection. En ordonnées, la charge virale exprimée en nombre de copies du génome du virus SARS-CoV-2 par µL. En abscisse, les groupes d’animaux, de droite à gauche (i) les animaux témoins infectés par SARS-CoV-2 non traités par F. prausnitzii et (ii) les animaux infectés par SARS-CoV-2 et traités par F. prausnitzii. La différence est statistiquement significative avec une valeur de P de 0,0006. La Figure 2 représente la charge virale en virus SARS-CoV-2 de hamsters, quatre jours après l’infection. En ordonnées, la charge virale exprimée en nombre de particules du virus SARS-CoV-2 par mL. En abscisse, les groupes d’animaux, de droite à gauche (i) les animaux témoins infectés par SARS-CoV-2 non traités par F. prausnitzii et (ii) les animaux infectés par SARS-CoV-2 et traités par F. prausnitzii. La différence est statistiquement significative avec une valeur de P de 0,01. La Figure 3 représente la perte de poids induite par une infection virale par IAV chez des souris mâles C57BL/6J âgées de 8 semaines, soit en cinétique après l’infection (Fig. 3A) soit à J7 post-infection (Fig. 3B). Les résultats obtenus dans trois groupes d’animaux sont représentés : un groupe témoin non infecté par le virus (groupe Non infecté), un groupe contrôle infecté par IAV mais non traité (groupe infecté IAV) et un group infecté par IAV et ayant reçu un traitement de F. prausnitzii selon l’invention (groupe IAV F. prausnitzii A2.165). Figure 3A : Abscisse : jours. Ordonnée : % du poids initial des souris. Figure 3B :
Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii A2.165. Ordonnée : % de perte de poids des souris. La Figure 4 représente la charge virale évaluée en nombre de copies du génome de IAV par qRT-PCR spécifique (Taqman). Les données sont montrées en valeur linéaire (Fig. 4A) ou logarithmique (Fig. 4B). Les résultats obtenus dans trois groupes d’animaux sont représentés : un groupe témoin non infecté par le virus (groupe Non infecté), un groupe contrôle infecté par IAV mais non traité (groupe infecté IAV) et un group infecté par IAV et ayant reçu un traitement de F. prausnitzii selon l’invention (groupe IAV F. prausnitzii A2.165). Figure 4A : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii A2.165. Ordonnée : Nombre de copies de IAV (gène M1). Figure 4B : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii A2.165. Ordonnée : Nombre de copies de IAV (gène M1) en Log10. *** : p< 0.001 ; **** : p < 0.0001 La Figure 5 représente le score clinique évalué par analyses histologiques sur des coupes de poumon colorées par l’hématoxyline et à l'éosine (H&E). Cette analyse montre une baisse significative (* : p< 0.05) des scores totaux (Fig. 5A), majoritairement dus à une baisse significative (* : p< 0.05) du pourcentage de lésions pulmonaires (Fig 5B), ainsi qu’une baisse significative du score d’inflammation vasculaire (p=0.09) (Fig 5C), chez les souris traitées par la souche F. prausnitzii A2-165 (groupe IAV F. prausnitzii A2.165). Les mêmes groupes qu’indiqués précédemment sont représentés. Abscisse pour les Figures 5A, 5B et 5C : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii A2.165. Ordonnée pour 5A : scores totaux. Ordonnée pour 5B : pourcentage de lésions. Ordonnée pour 5C : Scores. La Figure 6 représente l’expression des gènes codant pour l’Interféron beta (Ifnb – Figure 6A) et des gènes induits par l’interféron gamma (Mx1 et Isg15 – respectivement Figures 6B et 6C), gènes liés à l’infection virale, évaluée par qRT-PCR. Les mêmes groupes qu’indiqués précédemment sont représentés. Abscisse pour les Figures 6A, 6B et 6C : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii A2- 165. Ordonnée pour 6A : Expression relative en Ifnb. Ordonnée pour 6B : Expression relative en Mx1. Ordonnée pour 6C : Expression relative en Isg15. La Figure 7 montre l’expression des gènes pro-inflammatoires codant deux chimiokines impliquées dans le recrutement de cellules inflammatoires : MCP1/CCL2
(Figure 7A) et CXCL2 (Figure 7B), évaluée par qRT-PCR. Les mêmes groupes qu’indiqués précédemment sont représentés. Abscisse pour les Figures 7A et 7B : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii A2-165. Ordonnée pour 7A : Expression relative en Mcp1/Ccl2. Ordonnée pour 7B : Expression relative en Cxcl2. La Figure 8 représente la perte de poids induite par une infection virale par IAV chez des souris mâles C57BL/6J âgées de 8 semaines, soit en cinétique après l’infection (Fig. 8A) soit à J7 post-infection (Fig. 8B). Les résultats obtenus dans quatre groupes d’animaux sont représentés : un groupe témoin non infecté par le virus (groupe Non infecté), un groupe contrôle infecté par IAV mais non traité (groupe infecté IAV), un group infecté par IAV et ayant reçu un traitement de F. prausnitzii A2-165 vivante selon l’invention (groupe IAV F. prausnitzii A2-165 vivant) et un group infecté par IAV et ayant reçu un traitement de F. prausnitzii A2-165 inactivée (pasteurisée) selon l’invention (groupe IAV F. prausnitzii A2- 165 pasteurisé). Figure 8A : Abscisse : jours post infection. Ordonnée : % du poids initial des souris. Figure 8B : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV, groupe IAV F. prausnitzii A2-165 vivant et groupe infecté IAV, groupe IAV F. prausnitzii A2-165 pasteurisé. Ordonnée : % de perte de poids des souris. La Figure 9 représente la charge virale évaluée en nombre de copies du génome de IAV par qRT-PCR spécifique (Taqman). Les données sont montrées en valeur linéaire (Fig. 9A) ou logarithmique (Fig. 9B). (**** = p< 0.001 ; ** = p< 0.01) de la charge virale par comparaison aux animaux qui n’ont pas reçus de F. prausnitzii. Les résultats obtenus dans quatre groupes d’animaux sont représentés : un groupe témoin non infecté par le virus (groupe Non infecté), un groupe contrôle infecté par IAV mais non traité (groupe infecté IAV), un groupe infecté par IAV et ayant reçu un traitement de F. prausnitzii A2-165 vivant selon l’invention (groupe IAV F. prausnitzii A2.165 vivant) et un groupe infecté par IAV et ayant reçu un traitement de F. prausnitzii A2-165 pasteurisé selon l’invention (groupe IAV F. prausnitzii A2.165 pasteurisé). Figure 9A : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV, groupe IAV F. prausnitzii A2.165 vivant et groupe IAV F. prausnitzii A2.165 pasteurisé. Ordonnée : Nombre de copies de IAV (gène M1). Figure 9B : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV, groupe IAV F. prausnitzii A2.165 vivant et groupe IAV F. prausnitzii A2.165 pasteurisé. Ordonnée : Nombre de copies de IAV (gène M1) en Log10.
La Figure 10 représente la perte de poids induite par une infection virale par IAV chez des souris mâles C57BL/6J âgées de 8 semaines, soit en cinétique après l’infection (Fig. 10A) soit à J7 post-infection (Fig. 10B). Les résultats obtenus dans trois groupes d’animaux sont représentés : un groupe témoin non infecté par le virus (groupe Non infecté), un groupe contrôle infecté par IAV mais non traité (groupe infecté IAV) et un group infecté par IAV et ayant reçu un traitement de F. prausnitzii I-4574 selon l’invention (groupe IAV F. prausnitzii I-4574). Figure 10A : Abscisse : jours post infection. Ordonnée : % du poids initial des souris. Figure 10B : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii I-4574. Ordonnée : % de perte de poids des souris. La Figure 11 représente la charge virale évaluée en nombre de copies du génome de IAV par qRT-PCR spécifique (Taqman). Les données sont montrées en valeur linéaire (Fig. 11A) ou logarithmique (Fig. 11B). (** = p< 0.01) de la charge virale par comparaison aux animaux qui n’ont pas reçus de F. prausnitzii. Les résultats obtenus dans trois groupes d’animaux sont représentés : un groupe témoin non infecté par le virus (groupe Non infecté), un groupe contrôle infecté par IAV mais non traité (groupe infecté IAV) et un groupe infecté par IAV et ayant reçu un traitement de F. prausnitzii I-4574 selon l’invention (groupe IAV F. prausnitzii I-4574). Figures 11A et 11B : Abscisse : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii I-4574. Ordonnée Figure 11A : Nombre de copies de IAV (gène M1). Ordonnée Figure 11B : Nombre de copies de IAV (gène M1) en Log10. La Figure 12 représente l’expression des gènes codant pour l’Interféron gamma (Ifng – Figure 12A) et l’Interféron beta (Ifnb – Figure 12B) et du gène induit par l’interféron gamma (Isg15 Figures 12C), gène lié à l’infection virale, évaluée par qRT-PCR. Les mêmes groupes qu’indiqués précédemment sont représentés. Abscisse pour les Figures 12A, 12B et 12C : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F. prausnitzii I-4574. Ordonnée pour 12A : Expression relative en Ifng. Ordonnée pour 12B : Expression relative en Ifnb. Ordonnée pour 12C : Expression relative en Isg15. La Figure 13 montre l’expression des gènes pro-inflammatoires : Il6 (Figure 13A), MCP1/CCL2 (Figure 13B) et CXCL2 (Figure 13C), évaluée par qRT-PCR. Les mêmes groupes qu’indiqués précédemment sont représentés. Abscisse pour les Figures 13A, 13B et 13C : de gauche à droite : groupe Non infecté, groupe infecté IAV et groupe IAV F.
prausnitzii I-4574. Ordonnée pour 13A : Expression relative en Mcp1/Ccl2. Ordonnée pour 13B : Expression relative en Mcp1/Ccl2. Ordonnée pour 13C : Expression relative en Cxcl2. Description détaillée Les inventeurs ont montré que l’apport de bactéries du genre Faecalibacterium, en particulier des bactéries de l’espèce Faecalibacterium prausnitzii (aussi appelée F. prausnitzii dans la présente description) à des sujets infectés par un virus respiratoire, en particulier de sujets infectés par un virus SARS-CoV-2 et chez des sujets infectés par le virus de l’influenza, provoque une réduction très importante de la charge virale du sujet, en particulier une réduction très importante de la charge virale pulmonaire du sujet. De plus, il est montré qu’un apport de bactéries du genre Faecalibacterium, en particulier de bactéries de l’espèce F. prausnitzii, préalable à une infection par un virus respiratoire, en particulier préalable à une infection par un virus SARS-CoV-2, permet une charge virale réduite du sujet qui est subséquemment infecté , en particulier permet une charge virale pulmonaire réduite du sujet qui est subséquemment infecté, par comparaison avec un sujet infecté dans les mêmes conditions par ledit virus respiratoire mais qui n’a pas reçu ledit apport de bactéries du genre Faecalibacterium. La charge virale réduite qui est observée est illustrée à la fois (i) par une diminution du nombre de copies du génome viral et (ii) par une diminution du nombre de particules virales, en particulier dans les poumons. Les inventeurs ont aussi montré que l’apport de bactéries du genre Faecalibacterium, en particulier de bactéries de l’espèce F. prausnitzii, permet de réduire, chez un sujet, la présence ou l’étendue de lésions pulmonaires provoquées par une infection du sujet par un virus respiratoire, tel que SARS-CoV-2 ou Influenza. Il est également montré dans les exemples que l’apport de bactéries du genre Faecalibacterium, en particulier de bactéries de l’espèce F. prausnitzii, permet de réduire, chez un sujet, l’inflammation vasculaire provoquée par une infection du sujet par un virus respiratoire, tel que SARS-CoV-2 ou Influenza. Les inventeurs ont également montré que l’apport de bactéries du genre Faecalibacterium, en particulier de bactéries de l’espèce F. prausnitzii, spécialement chez des sujets infectés par un virus respiratoire tel que SARS-CoV-2 ou Influenza, induisent un accroissement du niveau d’expression de gènes impliqués dans la réponse anti-virale de
l’hôte, tels que les gênes suivant : (i) le gène Ifng codant l’interféron gamma, (ii) le gène Ifnb l’interféron beta, (iii) le gène IfnI3 codant l’interféron lambda 3, (iv) le gène Mx1 codant la protéine Mx1 se liant au GTP et qui est induite par l’interféron, (v) le gène Isg15 qui est stimulé par l’interféron ou encore (vi) le gène STAT1 qui est activé par les interférons de type 1. A la connaissance du demandeur, l’effet direct sur une infection virale de bactéries du genre Faecalibacterium, et en particulier l’effet de ces bactéries sur la charge virale, et encore plus particulièrement sur la charge virale en un virus respiratoire, ni sur leurs effets sur lésions, en particulier pulmonaires, d’une infection par un virus respiratoire, n’a jamais été montré dans l’état de la technique. La présente invention concerne des bactéries du genre Faecalibacterium pour leur utilisation pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Les bactéries du genre Faecalibacterium peuvent être choisies parmi les bactéries de l’espèce F. prausnitzii et les bactéries de l’espèce F. duncaniae. La présente invention concerne des bactéries du genre Faecalibacterium pour leur utilisation, en tant qu’agent antiviral, pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Les bactéries du genre Faecalibacterium peuvent être choisies parmi les bactéries de l’espèce F. prausnitzii et les bactéries de l’espèce F. duncaniae. Elle est relative à l’utilisation des bactéries du genre Faecalibacterium pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Elle est relative à l’utilisation des bactéries du genre Faecalibacterium pour la prévention ou le traitement, en tant qu’agent antiviral, d’une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Elle a trait à l’utilisation des bactéries du genre Faecalibacterium pour la fabrication d’un médicament pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain.
Elle a trait à l’utilisation des bactéries du genre Faecalibacterium pour la fabrication d’un médicament pour la prévention ou le traitement, en tant qu’agent antiviral, d’une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Elle concerne une méthode pour prévenir ou traiter une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain, comprenant une étape au cours de laquelle il est apporté au sujet des bactéries du genre Faecalibacterium. Elle concerne une méthode pour prévenir ou traiter une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain, comprenant une étape au cours de laquelle il est apporté au sujet des bactéries du genre Faecalibacterium en tant qu’agent antiviral. La présente invention concerne des bactéries du genre Faecalibacterium pour réduire les lésions de l’organisme, en particulier pour réduire les lésions pulmonaires, provoquées par une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Elle est relative à l’utilisation des bactéries du genre Faecalibacterium pour réduire les lésions de l’organisme, en particulier pour réduire les lésions pulmonaires, provoquées par une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Elle a trait à l’utilisation des bactéries du genre Faecalibacterium pour la fabrication d’un médicament pour réduire les lésions de l’organisme, en particulier pour réduire les lésions pulmonaires, provoquées par une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain. Elle concerne une méthode pour réduire les lésions de l’organisme, en particulier pour réduire les lésions pulmonaires, provoquées par une infection d’un sujet par un virus respiratoire, ce qui inclut une infection par un virus respiratoire de préférence humain, comprenant une étape au cours de laquelle il est apporté au sujet des bactéries du genre Faecalibacterium. Par prévention ou traitement « d’une infection d’un sujet » par un virus respiratoire, on entend selon la présente description un effet prophylactique ou thérapeutique sur le niveau d’une infection par un virus respiratoire lors de la survenue de l’infection, et
plus particulièrement un effet prophylactique ou thérapeutique sur le niveau de charge virale du sujet, après la survenue d’une infection par un virus, ici un virus respiratoire. Par « sujet», on entend selon la description un sujet choisi parmi les humains et les animaux. Les animaux englobent les mammifères non humains qui appartiennent au groupe des animaux de rente, d’élevage ou de compagnie, comme par exemple un canidé, un félidé ou un équidé. De manière tout à fait préférée, un sujet est un être humain. Par « virus humain », on entend un virus ayant la capacité à infecter un sujet humain. Par « virus non-humain », on entend un virus ayant la capacité d’infecter un sujet non-humain, c’est-à-dire un animal. Il est précisé que certains des virus d’intérêt pour la présente description sont à la fois des virus humains et des virus non-humains, comme par exemple le MERS-CoV. Par « agent antiviral », on entend un agent apte à réduire la charge virale d’un sujet, ce qui englobe que l’agent antiviral est apte à (i) réduire le nombre de copies du génome viral et/ou (ii) réduire le nombre de particules virales dans le corps du sujet infecté, ce qui inclut dans le tissu pulmonaire du sujet infecté. F. prausnitzii est un membre majeur du phylum Firmicutes et fait partie des bactéries commensales les plus abondantes dans le microbiote du gros intestin sain humain. F. prausnitzii est, en particulier, connu comme étant l’une des bactéries productrices de butyrate les plus abondantes dans le tube digestif humain, l’acide gras à chaîne courte butyrate étant très important dans la physiologie de l’intestin, des fonctions systémiques et des effets bénéfiques pour la santé humaine (Macfarlane et Macfarlane (2011), J. Clin. Gastroenterol. 45 Suppl : S120-7). Il a été très récemment proposé des changements dans la classification des bactéries du genre Faecalibacterium, la nouvelle classification proposée étant basée sur les caractéristiques du génome bactérien (Sakamoto et al., 2022, International Journal of Systematic and Evolutionary Microbiology, Vol. 72 : 005379 – Doi : 10.1099//jsem.0.005379). Dans ce cadre, par exemple, il est proposé que la bactérie Faecalibacterium prausnitzii A2-165 soit classée en tant que Faecalibacterium duncaniae.
Au sens de la présente description, les bactéries F. prausnitzii englobent les bactéries qui étaient classées comme appartenant à l’espèce F. prausnitzii à la date du 10 septembre 2021. Les bactéries du genre Faecalibacterium, en particulier les bactéries de l’espèce F prausnitzii, englobent celles référencées dans la demande PCT publiée sous le n° WO 2016/075294, ce qui inclut les bactéries déposées selon le Traité de Budapest à la Collection de Cultures de Microorganismes de l’Institut Pasteur soue les numéros d’accès I-4542, I- 4544, I-4540, I-4574, I-4543, I-4575, I-4573, I-4644 et I-4546. Les bactéries du genre Faecalibacterium, en particulier les bactéries de l’espèce F prausnitzii englobent aussi les souches déposées auprès de l’American Type Culture Collection (ATCC) sous le numéro d’accès ATCC 27768. Les bactéries du genre Faecalibacterium peuvent être des bactéries de la souche A2-165 déposée à la Collection allemande de Cultures de cellules et de Microorganismes (DMSZ) sous le numéro d’accès DSM 17677. Les bactéries du genre Faecalibacterium peuvent être des bactéries vivantes, des bactéries inactivées ou des bactéries mortes. Dans certains modes de réalisation, les bactéries du genre Faecalibacterium sont des bactéries vivantes. Par « bactéries vivantes », on entend selon la présente description, des bactéries capables de se multiplier, dans des conditions appropriées. Dans certains autres modes de réalisation, les bactéries du genre Faecalibacterium sont des bactéries inactivées ou des bactéries mortes. Selon la présente description, des bactéries « inactivées » ne sont pas capables, au moins de manière transitoire, ce qui inclut de manière définitive, de former des colonies en culture, dans des conditions de culture appropriées. Selon la présente description, des bactéries « mortes » sont des bactéries qui ne sont plus, de manière permanente et définitive, capables de former des colonies en culture, dans des conditions de culture appropriées. Des bactéries inactivées ou des bactéries mortes peuvent posséder des parois membranaires intactes ou, au moins partiellement, rompues. Des bactéries inactivées peuvent être préparées par exposition des cellules bactériennes à une irradiation, par exemple par un rayonnement ionisant, par inactivation
thermique, par inactivation acide ou basique, par inactivation par exposition à l’air ou à l’oxygène, ou encore par lyophilisation. Chacune de ces méthodes d’inactivation de bactéries est bien connue de l’homme du métier. L’inactivation par irradiation peut être réalisée par exposition des bactéries à une rayonnement gamma, à des rayons X, ou encore par exposition à un rayonnement UV. Des bactéries inactivées par lyophilisation peuvent être réactivées et remises en culture. L’inactivation thermique peut être réalisée par incubation des bactéries du genre Faecalibacterium pendant une période prolongée, par exemple au moins deux heures, à 170° C. L’inactivation thermique peut également être réalisée par autoclavage, en soumettant les bactéries du genre Faecalibacterium à une température de 121° C pendant une période d’au moins 20 minutes et à une pression atmosphérique de 2 bars. Sont englobés également les procédés d’inactivation thermique tels que la pasteurisation ou la tyndallisation. Alternativement, l’inactivation thermique peut être réalisée en soumettant les bactéries du genre Faecalibacterium à une température de congélation, pendant une période de temps prolongée. L’inactivation par le pH peut être réalisée en incubant les bactéries du genre Faecalibacterium pendant une période de temps prolongée dans un pH faible ou élevé, par exemple pendant 30 min à pH 2. L’inactivation par exposition à l’air peut être réalisée carles bactéries du genre Faecalibacterium, en particulier Faecalibacterium prausnitzii, sont des organismes extrêmement sensibles à l’oxygène (EOS). Le processus peut être réalisé en incubant pendant un certain temps la bactérie en question dans une atmosphère d’air. La présente description englobe aussi non seulement l’utilisation des bactéries du genre Faecalibacterium, mais aussi l’utilisation d’un extrait bactérien ou d’un lysat bactérien obtenu à partir de bactéries du genre Faecalibacterium, pour chacune des utilisations de bactéries du genre Faecalibacterium qui est décrite dans cette description. Un extrait ou un lysat qui convient aux utilisations spécifiées dans la présente description peut être préparé à partir des bactéries du genre Faecalibacterium, à la fin de la phase de croissance. Une souche bactérienne qui convient pour une utilisation spécifiée dans la présente description peut être utilisée sous la forme d’un lysat.
Au sens de l’invention, un « lysat » désigne communément un matériau obtenu après destruction ou dissolution de cellules biologiques par un phénomène connu sous le nom de lyse cellulaire, donnant ainsi lieu à la libération des constituants biologiques intracellulaires naturellement contenus dans les cellules de la bactérie considérée. Dans le cadre de la présente description, le terme « lysat » est utilisé sans préférence pour désigner le lysat entier obtenu par lyse de la bactérie considérée ou seulement une fraction de celui-ci. Le lysat utilisé est donc totalement ou partiellement formé des constituants biologiques intracellulaires et des constituants des parois et membranes cellulaires des bactéries. Au sens de la présente description, le terme « fraction » désigne plus particulièrement des fragments de ladite bactérie. Dans un mode de réalisation particulier, un lysat selon la présente description peut être le lysat entier obtenu par lyse des souches bactériennes considérées. Cette lyse cellulaire peut être réalisée par différentes techniques connues, telles qu’un choc osmotique, un choc thermique, par exposition à des ultrasons, ou alternativement sous une contrainte mécanique de type centrifugation. En particulier, un lysat selon la présente description peut être obtenu par désintégration ultrasonique d’un milieu comprenant des bactéries du genre Faecalibacterium, en particulier des bactéries de l’espèce F. pausnitzii ou de l’espèce F. duncaniae, en suspension afin d’en libérer les fractions cytoplasmiques, les fragments de paroi cellulaire et les produits issus du métabolisme. Tous les composants dans leur distribution naturelle sont ensuite stabilisés dans une solution aqueuse faiblement acide. Il est précisé que les techniques ci-dessus, illustrées pour les bactéries du genre Faecalibacterium, peuvent également être utilisées pour tuer ou inactiver des bactéries d’autres espèces, susceptibles d’être combinées à Faecalibacterium, en particulier à F. prausnitzii ou F. duncaniae, dans une composition d’intérêt spécifiée dans la présente description. Les virus respiratoires sont de préférence choisis parmi les virus respiratoires provoquant un syndrome aigu sévère de détresse respiratoire. Les virus respiratoires engobent (i) les virus respiratoires infectant les sujets humains et (ii) les virus respiratoires infectant les sujets non humains, c’est-à-dire les animaux et plus spécialement les
mammifères non humains, comme par exemple, sans être limitatif, des bovins, des ovins, des porcins, des canins, des félins ou encore des équins. Les virus respiratoires, y compris les virus respiratoires humains, peuvent être choisis, à titre d’exemples non limitatifs, parmi (i) un virus respiratoire syncitial humain (HRSV), (ii) un virus humain parainfluenza (HPIV), (iii) un rhinovirus humain (HRV), (iv) un virus de la maladie Aléoutienne (ADV), (v) un coronavirus humain (HcoV), (vi) un metapneumovirus humain (HPMV), (vii) un bocavirus humain (HboV), (viii) un virus parainfluenza humain (HIPV), (ix) un virus de l’influenza humain (IAV), (x) les rotavirus, (xi) les calicivirus, (xii) les torovirus, (xiii) les adenovirus, (xiv) les herpesvirus BHV et ADV et (xv) les pestivirus. Les rotavirus peuvent être choisis parmi les virus RVA, RVB, RVC et RVH. Le calicivirus peuvent être choisis parmi les novovirus et les sapovirus. Les pestivirus peuvent être choisis parmi les virus BVDV et CSFV. Les coronavirus sont choisis parmi (i) les coronavirus infectant les sujets humains et (ii) les coronavirus infectant les sujets non humains, ce qui inclut les mammifères non-humains. L’homme du métier peut notamment se référer à l’article de revue de Khbou et al. (2021, Vet Med Sci, Vol. 7 : 322-347). Les coronavirus infectant des sujets non humains peuvent être choisis, à titre d’exemples non limitatifs, parmi (i) les coronavirus bovins, tel que le coronavirus bovin (BcoV), (ii) les coroonavirus infectant les buffles, tel que le Bubaline coronavirus (BuCoV), (iii) les coronavirus infectant les dromadaires, tel que le Middle East respiratory syndrome coronavirus (MERS-CoV), (iv) les coronavirus infectant les équins, tel que l’Equine coronavirus (EcoV), (v) les coronavirus infectant les lapins, tel que le Rabbit coronavirus (RbCoV), (vi) les coronavirus infectant les porcins, tels que le Porcine hemagglutinating encephalomyelitis virus (PHEV), le Transmissible gastroenteritis virus (TGEV), le Porcine respiratory coronavirus (PRCV), le Swine acute diarrhoea syndrome coronavirus (SADS- CoV), le Porcine epidemic diarrhoea virus (PEDV) et le Porcine delatocoronavirus (PDCov), (vii) les coronavirus infectant les poulets, tels que le Infectious bronchitis virus (IBV), (viii) les coronavirus infectant les dauphins, tel que le Bottlenoise whale (BdCoV), (ix) les coronavirus infectant les baleines, tel que le Beluga whale (BWCoV) et (x) les coronavirus infectant les phoques.
Les coronavirus humains sont choisis notamment parmi (i) un coronavirus du syndrome respiratoire du Moyen-Orient (MERS-CoV), et (ii) un coronavirus responsable du syndrome respiratoire aigu sévère (SARS-CoV). Les virus respiratoires SARS-CoV peuvent être choisis parmi les virus SARS- CoV-1 et les virus SARS-CoV-2. Ils sont de préférence des virus respiratoires SARS-CoV- 2. Les virus respiratoires peuvent être choisis parmi les virus Influenza, préférentiellement un virus de l’Influenza humain. Le virus de l’Influenza peut être un virus de l’un des types A, B ou C et est préférentiellement un virus de l’Influenza de type A (aussi appelé « IAV » dans la présente description). Il peut être un virus de l’Influenza de typa A, d’un sous-type choisi parmi A(H1N1) et A(H3N2). Il peut être un virus de l’Influenza de type B, d’un sous-type choisi parmi B (Victoria) et B (Yamagata). Les espèces de virus respiratoires, de préférence les espèces de virus respiratoires humains, englobent les différentes souches, parfois dénommées « variants », desdits virus. A titre d’illustration, les virus du type SARS-CoV-2 englobent les différentes souches, parfois dénommées « variants », de ces virus. De manière similaire, un virus de l’Influenza appartenant à un sous-type donné, est répertorié selon un sous-classement dans des clades (groupes), puis dans des sous-clades (sous-groupes). A titre illustratif, un virus de l’Influenza de type A (IAV) peut être classé dans le sous-type A(H1N1), puis dans la clade 68.1 et enfin dans la sous-clade 68.1.A. De même, des souches de virus de l’Influenza de type A (IAV) peuvent être classées dans le sous-type A(H3N2) L’invention est relative à des bactéries du genre Faecalibacterium pour leur utilisation pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, de préférence par un virus respiratoire humain, pour réduire la charge virale du sujet en ledit virus respiratoire au cours de l’infection. Les bactéries du genre Faecalibacterium peuvent être choisies parmi les bactéries de l’espèce F. prausnitzii et les bactéries de l’espèce F. duncaniae. L’invention concerne l’utilisation de bactéries du genre Faecalibacterium pour la fabrication d’un médicament pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, de préférence par un virus respiratoire humain, pour réduire la charge virale du sujet en ledit virus respiratoire au cours de l’infection.
L’invention a trait à une méthode pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, pour réduire la charge virale du sujet au cours de l’infection, comprenant une étape d’apport audit sujet de bactéries du genre Faecalibacterium. L’invention a aussi trait à une méthode prophylactique ou thérapeutique pour l’obtention d’une charge virale réduite d’un sujet lorsqu’il est infecté par un virus respiratoire, ladite méthode comprenant une étape d’apport audit sujet de bactéries du genre Faecalibacterium. Par « charge virale » d’un sujet au sens de la présente description, on entend une quantité de virus présent dans un tissu et/ou un organe dudit sujet. De manière préférée, au sens de la présente description, la charge virale du sujet consiste en une quantité de virus présent dans le tissu pulmonaire et/ou dans le fluide pulmonaire dudit sujet. Au sens de la présente description, une quantité de virus peut être exprimée (i) en nombre de copies de génome viral ou (ii) en nombre de particules virales infectieuses. Comme cela est connu, le nombre de copies de génome viral peut être déterminé selon une méthode comprenant une étape d’amplification de l’ARN viral, de préférence selon la technique de RT-PCR, comme illustré dans les exemples. Comme cela est connu, le nombre de particules virales infectieuses peut être déterminé selon une méthode de titration des particules virales comprenant une étape d’infection de cellules sensibles aux dit virus. Les résultats peuvent être exprimés en TCID50/mL, soit en quantité de virus nécessaire pour provoquer l’infection de 50% des cellules sensibles. Au sens de la présente description, la charge virale d’un sujet est réduite lorsqu’une diminution d’au moins 5 fois, mieux d’au moins 10 fois, la charge virale de référence est mesurée, par rapport à une valeur de référence. Par exemple, une réduction de la charge virale d’un sujet en un virus respiratoire est attestée lorsque qu’une diminution d’au moins 5 fois le nombre de copies du génome dudit virus, mieux d’au moins 10 fois le nombre de copies du génome dudit virus est mesurée, par rapport à une valeur de référence. Également, une réduction de la charge virale d’un sujet en un virus respiratoire est attestée lorsque qu’une diminution d’au moins 5 fois le nombre de particules dudit virus,
mieux d’au moins 10 fois le nombre de particules dudit virus, est mesurée, par rapport à une valeur de référence. Comme cela est illustré dans les exemples, un apport en bactéries du genre Faecalibacterium a la propriété, chez un sujet infecté par un virus respiratoire, en particulier infecté par un virus SARS-CoV-2, de réduire de plus de 10 fois la charge virale, par rapport à un sujet qui n’a pas reçu un apport en bactéries du genre Faecalibacterium, que cette charge virale soit exprimée (i) en nombre de copies du génome viral ou (ii) en nombre de particules virales. Compositions La présente invention concerne en outre une composition comprenant, dans un milieu physiologiquement acceptable, au moins des bactéries du genre Faecalibacterium, notamment des bactéries de l’espèce F prausnitzii ou des bactéries de l’espèce F. duncaniae. Préférentiellement, une composition selon la présente description possède une formulation adaptée pour son administration par voie intra-nasale, orale ou rectale. Les bactéries du genre Faecalibacterium appropriées sont décrites ailleurs dans la présente description. Dans certains modes de réalisation d’une composition selon la description, la souche choisie de Faecalibacterium, notamment de F. prausnitzii ou de F. duncaniae, est utilisée comme la seule souche bactérienne présente dans la composition. Dans certains modes de réalisation une combinaison de plusieurs souches de Faecalibacterium, notamment de F. prausnitzii ou de F. duncaniae, sont les seules souches bactériennes présentes dans la composition. Dans certains autres modes de réalisation d’une composition selon la description, les bactéries de Faecalibacterium, notamment de F. prausnitzii ou de F. duncaniae, sont combinées à des bactéries d’une ou plusieurs autres souches bactériennes probiotiques, ce qui englobe d’autres souches bactériennes probiotiques commensales. Des exemples non limitatifs de probiotiques englobent les souches de bactéries appartenant aux genres suivants : Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, et de trois levures Kluyveromyces, Saccharomyces, Candida et leurs combinaisons.
Les probiotiques peuvent être choisis dans le groupe constitué par les espèces bactériennes suivantes : Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei (désormais Lacticaseibacillus casei), Lactobacillus paracasei (désormais Lacticaseibacillus paracasei), Lactobacillus salivarius (désormais Ligilactobacillus salivarius), Lactobacillus lactis (désormais Lactobacillus delbrueckii subsp. Lactis), Lactobacillus rhamnosus (désormais Lacticaseibacillus rhamnosus), Lactobacillus johnsonii, Lactobacillus plantarum (désormais Lactiplantibacillus plantarum subsp. Plantarum), Lactococcus lactis, Enterococcus faecium, Enterococcus faecalis, Saccharomyces cerevisiae, Saccharomyces boulardii ou leurs mélanges, de préférence choisis dans le groupe constitué par Bifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longum NCC2705 (CNCM 1-2618), Bifidobacterium longum NCC490 (CNCM 1-2170), Bifidobacterium lactis NCC2818 (CNCM I- 3446), Bifidobacterium breve souche A, Lactobacillus paracasei NCC2461 (CNCM 1-2116), Lactobacillus johnsonsii NCC533 (CNCM 1-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CGMCC 1. 3724), Enterococcus faecium SF 68 (NCC2768 ; NCIMB10415), Faecalibacterium prausnitzii et leurs combinaisons. Dans certains modes de réalisation, une composition selon la présente description est combinée, par exemple dans un kit, avec un ou plusieurs autres agents utiles pour le traitement d’une infection d’un sujet par un virus SARS-CoV-2. Ces modes de réalisation englobent ceux dans lesquels une composition selon la présente description est combinée, par exemple dans un kit, avec un ou plusieurs anticorps dirigés contre un virus SARS-CoV-2. Ces modes de réalisation englobent aussi ceux dans lesquels une composition selon la présente description est combinée, par exemple dans un kit, avec un ou plusieurs agents anti-viraux. Dans certains modes de réalisation, la composition comprend aussi un ou plusieurs prébiotiques. Le terme « prébiotique » est utilisé dans son sens conventionnel dans l’état de la technique. Les prébiotiques consistent en des substances alimentaires favorisant la croissance de bactéries probiotiques, y compris les bactéries comprises dans le microbiote. Des exemples non limitatifs de prébiotiques comprennent : les oligosaccharides contenant éventuellement du fructose, du galactose, du mannose ; les fibres alimentaires, en particulier les fibres fermentescibles, les fibres de soja ; l’inuline ; et leurs combinaisons.
Les prébiotiques préférés sont les fructo-oligosaccharides (FOS), les galacto- oligosaccharides (GOS), les isomalto-oligosaccharides (IMO), les xylo-oligosaccharides (XOS), les arabino-xylo-oligosaccharides (AXOS), les mannan-oligosaccharides (MOS), les oligosaccharides de soja, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose-oligosaccharides (PAO), malto-oligosaccharides, les amidons résistants, les gommes et/ou hydrolysats de celles-ci, pectines et/ou hydrolysats de celles-ci, ou des combinaisons de ceux-ci. Dans certains modes de réalisation, la composition comprend de plus une ou plusieurs vitamines. Les vitamines peuvent être l’acide folique, la vitamine B12 et la vitamine B6, en particulier l’acide folique et la vitamine B12, en particulier l’acide folique. Dans certains modes de réalisation, la composition comprend une ou plusieurs vitamines qui sont liposolubles, par exemple une ou plusieurs vitamines parmi la vitamine A, la vitamine D, la vitamine E et la vitamine K. Dans certains modes de réalisation, la composition comprend un ou plusieurs polyphénols, tels que les flavanols, les flavanones, les flavonols, les acides hydroxycinnamiques et les anthocyanes. Dans certains modes de réalisation, la composition comprend en outre un ou plusieurs minéraux. Les minéraux peuvent être choisis parmi le sodium, le potassium, le chlorure, le calcium, le phosphate, le magnésium, le fer, le zinc, le cuivre, le sélénium, le manganèse, le fluor, l’iode, le chrome ou le molybdène. Les minéraux sont généralement ajoutés sous forme de sel. Les minéraux peuvent être ajoutés seuls ou en combinaison. Dans certains modes de réalisation, une composition selon la présente description comprend généralement des supports ou des véhicules. Les « supports » ou « véhicules » désignent des matériaux adaptés à l’administration et comprennent tout matériau connu dans l’état de la technique, tel que, par exemple, tout liquide, gel, solvant, diluant liquide, agent solubilisant ou autre, qui est non toxique et qui n’interagit pas avec les composants de la composition de manière délétère. Des exemples de supports nutritionnellement acceptables comprennent, par exemple, l’eau, les solutions salines, les alcools, les silicones, les cires, la vaseline, les huiles végétales, les polyéthylèneglycols, le propylèneglycol, les liposomes, les sucres, la gélatine, le lactose, l’amylose, le stéarate de magnésium, le talc, les agents tensioactifs, l’acide silicique, la paraffine visqueuse, l’huile
de parfum, les monoglycérides et diglycérides d’acides gras, les esters d’acides gras de pétrole, l’hydroxyméthylcellulose, la polyvinylpyrrolidone, etc. Dans certains modes de réalisation, la composition comprend de plus tout autre ingrédient ou excipient connu pour être employé dans le type de composition en question. Des exemples non limitatifs de tels ingrédients comprennent : des protéines, des acides aminés, des glucides, des oligosaccharides, des lipides, des nucléotides, des nucléosides, d’autres vitamines, des minéraux et d’autres micronutriments. Dans certains modes de réalisation, la composition contient une source de glucides, par exemple sous forme des prébiotiques, ou s des prébiotiques lorsqu’ils sont présents dans la composition. Toute source de glucides que l’on trouve habituellement dans les préparations pour nourrissons, comme le lactose, le saccharose, la maltodextrine, l’amidon et leurs mélanges, peut être utilisée, bien que la source préférée de glucides soit le lactose. Dans certains modes de réalisation, une composition selon la présente description consiste en une composition nutritionnelle, par exemple en une composition nutritionnelle dont la constitution est adaptée pour nourrir un sujet humain ou bien un sujet mammifère non humain. De manière tout à fait préférée, dans ces modes de réalisation, la composition est une composition nutritionnelle pour un sujet humain. Avantageusement, une composition selon l’invention, prévue pour une administration orale, peut être pourvu d’un enrobage résistant au suc gastrique, afin d’assurer que la souche bactérienne de l’invention comprise dans ladite composition puisse traverser l’estomac endommagé. La libération de la souche bactérienne peut ainsi se produire pour la première fois dans le tractus intestinal supérieur. Dans certains modes de réalisation, la composition nutritionnelle est choisie parmi les compositions alimentaires complètes, les compléments alimentaires, les compositions nutraceutiques et autres. La composition de la présente description peut être utilisée en tant qu’ingrédient alimentaire et/ou ingrédient d’aliments pour sujets humains ou pour sujets mammifères non humains. L’ingrédient alimentaire peut se présenter sous la forme d’une solution ou d’un solide, selon l’utilisation et/ou le mode d’application et/ou le mode d’administration. Tel qu’il est utilisé ici, le terme « aliment » fait référence à des compositions diététiques liquides (c’est-à-dire des boissons), solides ou semi-solides, en particulier des compositions alimentaires totales (remplacement d’aliments), qui ne
nécessitent pas d’apport supplémentaire de nutriments ou des compositions de compléments alimentaires. Les compositions de compléments alimentaires ne remplacent pas complètement l’apport de nutriments par d’autres moyens. Tel qu’utilisé dans la présente description, le terme « ingrédient alimentaire » englobe une formulation qui est ou peut être ajoutée à des aliments fonctionnels ou à des denrées alimentaires en tant que complément alimentaire. Par « aliment nutritionnel » ou « nutraceutique » ou « fonctionnel », on entend une matière alimentaire qui contient de ingrédients ayant des effets bénéfiques sur la santé ou capables d’améliorer les fonctions physiologiques. Par « complément alimentaire », on entend une matière alimentaire ayant pour finalité de compléter un régime alimentaire normal. Un complément alimentaire est une source concentrée de nutriments ou d’autres substances ayant un effet nutritionnel ou physiologique, lorsqu’ils sont pris seuls ou en combinaison en petites quantités. Selon la présente description, « aliment fonctionnel » est utilisé pour désigner les matières alimentaires et les produits correspondants auxquels on attribue de l’importance non seulement en raison de leur valeur nutritionnelle et gustative mais aussi en raison de la présence d’ingrédients ayant des effets physiologiques bénéfiques. Dans certains modes de réalisation, la composition est un produit laitier fermenté ou un produit à base de lait, qui est de préférence administrée ou ingérée par voie orale une ou plusieurs fois par jour. Les produits laitiers fermentés comprennent les produits à base de lait, tels que (mais sans s’y limiter) les desserts, les yaourts, les boissons au yaourt, le fromage blanc, le kéfir, les boissons à base de lait fermenté, le babeurre, les fromages, les vinaigrettes, les pâtes à tartiner à faible teneur en matières grasses, le fromage frais, les boissons à base de soja, la crème glacée, etc. En variante, dans certains modes de réalisation, les compositions nutritionnelles et/ou de compléments nutritionnels peuvent être des produits non laitiers ou laitiers non fermentés. Les produits laitiers non fermentés peuvent inclure les crèmes glacées, les barres nutritionnelles et les assaisonnements, et autres. Les produits non laitiers peuvent comprendre des boissons en poudre et des barres nutritionnelles, etc. Les produits peuvent être fabriqués en utilisant des méthodes connues, telles que l’ajout d’une quantité efficace de bactéries F. prausnitzii, ou d’une combinaison de bactéries incluant des bactéries F. prausnitzii à une base alimentaire, telle que du lait écrémé ou du lait ou une composition à base de lait, et réaliser une fermentation selon toute technique connue. Dans certains modes de réalisation, la composition est une boisson qui peut être une boisson fonctionnelle ou une
boisson thérapeutique, une boisson désaltérante ou une boisson conventionnelle. À titre d’exemple, la composition selon la présente description peut être utilisée comme ingrédient pour des boissons gazeuses, un jus de fruit ou une boisson comprenant des protéines de lactosérum, des thés, des boissons au cacao, des boissons au lait, des yaourts y compris des yaourts à boire, des fromages, des crèmes glacées, des glaces à l’eau et des desserts, des confiseries, des biscuits, des gâteaux et des préparations pour gâteaux, des snacks, des aliments et boissons équilibrés, des glaçages, boisson de soja/jus acidifié, boisson au chocolat aseptique/rapportée, mélanges pour barres, préparations en poudre pour boissons, lait de soja et chocolat enrichi en calcium, boisson au café enrichie en calcium. Dans certains modes de réalisation, la composition comprend tout autre ingrédient ou excipient connu pour être employé dans le type de composition en question. Des exemples non limitatifs de tels ingrédients comprennent : des protéines, des acides aminés, des glucides, des oligosaccharides, des lipides, des prébiotiques ou des probiotiques, des nucléotides, des nucléosides, d’autres vitamines, des minéraux et d’autres micronutriments. Dans certains autres modes de réalisation, des bactéries F. prausnitzii, le cas échéant en combinaison avec des bactéries probiotiques d’une ou plusieurs autres souches, sont administrées au sujet sous la forme d’une composition pharmaceutique, laquelle composition pouvant consister en un produit de type Live Biotherapeutic product (LBP) reference : Front Med (Lausanne) Rouanet et al2020 Jun 19 ;7 :237. Doi : 10.3389/fmed.2020.00237. Par exemple, les bactéries d’intérêt peuvent être combinées avec des excipients pharmaceutiquement acceptables, et éventuellement des matrices à libération prolongée, telles que des polymères biodégradables, pour former des compositions thérapeutiques. Les termes « pharmaceutiquement » ou « pharmaceutiquement acceptable » désignent des entités moléculaires et des compositions qui ne produisent pas de réaction indésirable, de réaction allergique ou autre lorsqu’elles sont administrées à un mammifère, en particulier à l’homme, selon le cas. Un support ou excipient pharmaceutiquement acceptable désigne une charge, un diluant, un matériau d’encapsulation ou un auxiliaire de formulation non toxique, solide, semi-solide ou liquide, de n’importe quel type. Dans les compositions pharmaceutiques de la présente description pour une administration particulièrement par voie orale ou rectale, l’ingrédient actif ou la combinaison d’ingrédients actifs ingrédients actifs, peut être administré sous une forme d’administration unitaire, en
mélange avec des supports pharmaceutiques classiques, à des animaux et des êtres humains. Les formes d’administration unitaires appropriées comprennent les formes d’administration (i) par voie orale telles que les comprimés, les capsules de gel, les poudres, les granules et les suspensions ou solutions orales, y compris les formes d’administration sublinguale et buccale, (ii) par voie intranasale tels que les aérosols et (iii) par voie rectale tels que les suppositoires. La composition pharmaceutique doit être stable dans les conditions de fabrication et de stockage et doit être préservée de l’action contaminante des micro- organismes exogènes, tels que les bactéries pathogènes et les champignons. Au sens de la présente description, l’expression « quantité thérapeutiquement efficace », lorsqu’elle est utilisée, est une expression équivalente qui se réfère à la quantité d’une thérapie (par ex, un agent prophylactique ou thérapeutique), qui est suffisante pour réduire la gravité et/ou la durée d’une maladie, améliorer un ou plusieurs de ses symptômes, empêcher la progression d’une maladie ou provoquer la régression d’une maladie, ou qui est suffisante pour aboutir à la prévention du développement, de la récurrence, de l’apparition ou de la progression d’une maladie ou d’un ou plusieurs de ses symptômes, ou renforcer ou améliorer le ou les effets prophylactiques et/ou thérapeutiques d’une autre thérapie (par exemple, un autre agent thérapeutique) utile pour traiter une maladie. Typiquement, dans une composition pharmaceutique selon la présente description, les bactéries F. prausnitzii sont présentes en une quantité suffisante pour induire une réduction de la charge virale d’un virus respiratoire chez le sujet traité, lorsque ce sujet est infecté par ledit virus respiratoire, par rapport à la charge virale attendue chez un sujet n’ayant pas reçu lesdites bactéries F. prausnitzii. Dans une composition selon la description, qu’il s’agisse d’une composition nutritionnelle ou alimentaire, le cas échéant d’un complément alimentaire, ou qu’il s’agisse d’une composition pharmaceutique, la ou les bactéries, en particulier les bactéries F. prausnitzii, peuvent se présenter sous des formes variées, par exemple sous forme liquide ou sous forme de poudre. La ou les bactéries, en particulier les bactéries F. prausnitzii, peuvent se présenter sous forme lyophilisée. La quantité de bactéries Faecalibacterium, notamment de F. prausnitzii ou de F. duncaniae, qui est apportée au sujet peut être variable, selon l’état physiologique dudit sujet, et notamment selon que les bactéries sont administrées dans un but prophylactique ou dans
un but thérapeutique. La quantité de bactéries F. prausnitzii qui doit être apportée audit sujet peut être aisément adaptée par l’homme du métier. Dans des modes de réalisation préférés, que la composition soit une composition nutritionnelle ou une composition pharmaceutique, la composition comprend une quantité de bactéries du genre Faecalibacterium qui est appropriée pour un apport quotidien, de préférence un apport oral quotidien, d’au moins 107 unités formant colonies (ou « CFU » pour « Colony Forming Units »). Dans ces modes de réalisation préférés, l’apport quotidien, en particulier l’apport oral quotidien, en bactéries du genre Faecalibacterium est au plus de 1011 unités formant colonies (ou « CFU » pour « Colony Forming Units »). Ainsi, dans certains modes de réalisation préférés, la composition comprend une quantité de bactéries du genre Faecalibacterium allant de 107 unités formant colonies à 1011 unités formant colonies. Dans les modes de réalisation dans lesquels la composition comprend de plus d’autres bactéries probiotiques, la quantité de ces bactéries probiotiques est déterminée par l’homme du métier sur la base de ses connaissances générales. La quantité de ces autres bactéries probiotiques peut varier de 103 à 1013 autres bactéries probiotiques. Dans les modes de réalisation dans lesquelles les bactéries sont inactivées, mortes, ou encore sous la forme d’un extrait bactérien ou d’un lysat bactérien, la quantité d’apport quotidien est l’équivalent de la quantité de bactéries correspondant au nombre approprié de CFUs spécifié plus haut. Dans certains modes de réalisation, une composition selon la présente description comprend généralement des supports ou des véhicules. Les « supports » ou « véhicules » désignent des matériaux adaptés à l’administration et comprennent tout matériau connu dans l’état de la technique, tel que, par exemple, tout liquide, gel, solvant, diluant liquide, agent solubilisant ou autre, qui est non toxique et qui n’interagit pas avec les composants de la composition de manière délétère. Des exemples de supports nutritionnellement acceptables comprennent, par exemple, l’eau, les solutions salines, les alcools, les silicones, les cires, la vaseline, les huiles végétales, les polyéthylèneglycols, le propylèneglycol, les liposomes, les sucres, la gélatine, le lactose, l’amylose, le stéarate de magnésium, le talc, les agents tensioactifs, l’acide silicique, la paraffine visqueuse, l’huile
de parfum, les monoglycérides et diglycérides d’acides gras, les esters d’acides gras de pétrole, l’hydroxyméthylcellulose, la polyvinylpyrrolidone, etc. Dans d’autres modes de réalisation d’une composition selon la présente description, comme indiqué ailleurs, ladite composition se présente sous la forme d’une composition pharmaceutique comprenant un ou plusieurs excipients pharmaceutiquement acceptables. Une telle composition pharmaceutique peut être présentée sous la forme d’un emballage comprenant une pluralité d’unités de dosage. Le terme « unité de dosage » est utilisé dans son sens conventionnel en pharmacie (p. ex. une pilule, une gélule, un comprimé, le contenu d’une ampoule, etc.). Utilisations La présente description concerne les utilisations prophylactiques et les utilisations thérapeutiques d’une composition telle que définie dans la présente demande, à l’encontre d’une infection d’un sujet par un virus respiratoire, en particulier à l’encontre d’une infection d’un sujet humain par un virus respiratoire. Les caractéristiques de composition, y compris d’une composition prophylactique et d’une composition thérapeutique, y compris dans divers modes de réalisation, sont décrites en détail dans la présente description, ce qui inclut les quantités d’ingrédient(s) actif(s), spécialement les quantités de bactéries du genre Faecalibacterium, notamment de bactéries de l’espèce F. prausnitzii ou de bactéries de l’espèce F. duncaniae, comprises dans ces compositions. Dans certains modes de réalisation, une composition prophylactique et une composition thérapeutique selon la présente description peuvent avoir une constitution qualitative et quantitative en ingrédients actifs et en excipient(s) qui est identique, la seule distinction étant que la composition « prophylactique » est administrée, à titre préventif, à un sujet non infecté par un virus respiratoire alors que la même composition, cette fois qualifiée de « thérapeutique » est administrée à un sujet qui est infecté par un virus respiratoire. Dans certains modes de réalisation, une composition conforme à la présente description, le cas échéant sous la forme d’une composition de complément alimentaire, est formulée pour une administration quotidienne, par exemple pour une administration quotidienne en une ou deux prises, par exemple au moment des repas.
Dans certains modes de réalisation, une composition conforme à la présente description, en particulier une composition prophylactique conforme à la présente description, est administrée au sujet de manière chronique, pendant une longue période de temps, par exemple pendant plusieurs mois ou même pendant plusieurs années, aux fins de tempérer les conséquences de la survenue éventuelle d’une infection par un virus respiratoire, par exemple par un virus SARS-CoV-2 ou encore par un virus de l’Influenza, en particulier un virus de l’Influenza de type A (IAV). Dans certains modes de réalisation, une composition conforme à la présente description, en particulier une composition thérapeutique conforme à la présente description, est administrée à un sujet infecté par un virus respiratoire, (i) jusqu’à la disparition des symptômes provoqués par l’infection par ledit virus respiratoire ou bien (ii) jusqu’à ce que la présence dudit virus respiratoire chez ledit sujet devienne indétectable L’invention est décrite ci-dessous de façon plus détaillée au moyen des exemples suivants qui sont présentés à titre d’illustration uniquement. Exemples Exemple 1 : Effet de F. prausnitzii sur la charge virale d’un virus respiratoire A. Matériels et Méthodes A.1. Protocole de traitement Des hamsters femelles âgées de 6 semaines de la lignée RjHan :AURA obtenus auprès de Janvier Lab ont été utilisés pour l’expérience. Les hamsters ont été séparés en deux groupes. Un premier groupe de hamsters a été inoculé avec le virus SARS-CoV-2 (souche UCN1/identifiant GISAID EPI_ISL_911513), par injection intranasale d’une dose de 104 TCID50 du virus. Un second groupe de hamsters a été traité par administration orale de F. prausnitzii à raison d’une quantité quotidienne de F. prausnitzii de 109 unités formant colonies (UFCs), pendant les 5 jours précédents l’infection par le SARS-CoV-2, puis pendant les 4 jours suivant l’inoculation par le virus SARS-CoV-2. A J6, les hamsters ont été inoculés avec le virus SARS-CoV-2 (souche UCN1), par injection intranasale d’une dose de 104 TCID50 du virus, comme pour le premier groupe. Les animaux des deux groupes ont été sacrifiés à J4 suivant l’inoculation du virus SARS-CoV-2.
A.2. Protocoles de mesure de la charge virale L’évaluation de la charge virale du virus SARS-CoV-2 a été réalisée à partir d’échantillons pulmonaires prélevés sur les animaux le jour de leur sacrifice. La détection du génome viral de SARS-CoV-2 a été effectuée à l’aide d’une méthode de PCR en temps réel. La détection du génome viral de SARS-COV-2 repose sur l’amplification du gène E (position 26141-26253) par TaqMan RT-qPCR à l’aide d’un couple d’amorces nucléotidiques et une sonde TaqMan décrites par Corman et al. (2020), La méthode suivante a été réalisée : - L’ARN viral est extrait à partir de 140 µL de surnageant clarifié de broyat tissulaire d’organes (dilué au 1/50ème) (i.e. poumon) ou à partir d’un volume de 140 µL de fluides biologiques (i.e. écouvillon oropharyngé dilué dans un volume de 500µL de milieu DMEM contenant 1% d’antibiotiques). L’extraction de l’ARN viral est réalisée à l’aide du kit commercial Qiagen Viral RNA mini kit (Qiagen, France) selon les instructions du fabricant. Les amorces nucléotidiques et la sonde TaqMan suivantes ont été uti isées : - E_Sarbeco_F1 ACAGGTACGTTAATAGTTAATAGCGT (SEQ ID NO. 1) - E_Sarbeco_R2 ATATTGCAGCAGTACGCACACA (SEQ ID NO. 2) - E_Sarbeco_P1 ACACTAGCCATCCTTACTGCGCTCG [5']’am [3']BHQ-1 (SEQ ID NO. 3). Les couples d’amorces et la sonde TaqMan ont été décrits par Corman et al. Eurosurvei llance ; PMID:31992387. Les amorces permettent l’amplification du gène E (amplicon de 112-pB, position 26141-26253). La TaqMan RT-qPCR a été réalisée dans un volume total de 25 µL Les tests RT- qPCR TaqMan ont été réalisés dans un volume total de 25 µL contenant 2,’ μL d'ARN extrait, 12,5 µL de mélange réactionnel 2x, 1 µL de MgCl225 mM (Invitrogen), 4,’ µL d'eau exempte de RNase, 2 µL de chacune des amorces (10 µM), 0,25 µL de sonde (10 µM) et 0.25 μL d’enzyme (Quantitect Probe RT mix). Tous les essais ont été réalisés sur le thermocycleur en temps réel Rotor Gene Q MDx (Qiagen, Courtaboeuf, France). L'amplification a été réalisée selon les conditions de thermocyclage suivantes : 50 °C pendant 30 min pour la transcription inverse, suivie de 95 °C pendant 15 min puis de 45 cycles de 94 °C pendant 30 s, 55 °C pendant 30 s et 72 °C pendant 30 s. Des contrôles négatifs et positifs ont été inclus dans chaque PCR.
Une courbe standard a été réalisée pour chaque essai de la mani re suivante : réalisation d’une gamme de 5 dilutions au 1/10ème à partir d’un ARN de SARS COV-2 calibré titrant 4,10^6’copies/µL d'ARN. Le seuil Ct de 0,05 a été utilisé comme référence pour chaque tes’ RT-qPCR. L'efficacité, la pente et le coefficient de corrélation (R2) ont été déterminés avec le logiciel Rotor Gene. Toutes les réactions PCR ont été effectuées en duplicats. Le titrage de la souche virale SARS-CoV-2 a été effectuée par infection de cellules sensibles au virus selon la méth de suivante : Le titrage des particules virales infectieuses est réalisé sur microplaques 96 puits. Une suspension de cellules VeroE6, sensibles au virus SARS-CoV-2, a été réalisée dans du milieu DMEM contenant 10% de sérum de veau fœtal (SVF) et 1% d’antibiotiques (pénicilline /streptomycine /amphotéricine B) de façon à obtenir une concentration finale de 1.105 cellules par ml. Cette suspension cellulaire a été ensemencée, dans chaque puit de la microplaque, 24 he’res avant l'inoculation des échantillons. Les microplaques ont été incubées à 37°C dans une étuve contenant 5 % de CO2. Vingt-quatre heures après, une première dilution de l’échantillon au 1/10 est effectuée dans du milieu dit « complet », c’est-à-dire du DMEM complété avec du sérum de veau fœtal (10%) et un mélange pénicilline/streptomycine (1%). Puis à partir de cet échantillon dilué, des dilutions en série de facteur 4 sont réalisées dans du milieu complet. Les microplaques contenant la suspension cellulaire sont prélevées dans l’étuve. Le milieu a été retiré de chaque puits et immédiatement 50 µL de la suspension diluée au 1/10 et des dilutions sériées au quart de chaque échantillon ont été ajoutés dans chaque puit en 6 réplicats. Après ajout de l’inoculum, la plaque a été incubée à 37°C avec 5% de CO2 pendant une heure. Six puits non infectés ont été utilisés comme contrôle négatif indépendant. Une heure plus tard, les puits des microplaques ont été complétés avec du milieu DMEM complet. Après 3-4 jours post-inoculation, les plaques ont été lues sous un microscope en lumière blanche. L’infection virale des cellules sensibles par le virus SARS-CoV-2, provoque des effets cytopathogènes. Le titre du virus présent dans les échantillons, exprimé en TCID50/mL, a été déterminé en utilisant la formule de Spe rman-Kärber : [Math 1]
d ns laquelle : - log10 (dilution50) = logarithme de la dilution où il y a 50% de signal positif, c’est à dire 50% de plages de lyse - x0 = - (log10 de la plus faible dilution avec tous les puits négatifs) - d = log10 du pas de dilution - ri = nombre de puits négatifs - ni = nombre de réplicats C. Résultats Les résultats sont présentés dans chacune des figures 1 et 2. Les résultats des figures 1 et 2 montrent une diminution statistiquement significative de la charge virale chez les animaux du second groupe qui a été traité avec F. prausnitzii, par comparaison aux animaux du second groupe qui n’ont pas reçus de F. prausnitzii, que la charge virale soit évaluée en nombre de copies du génome de SARS-CoV- 2 ou en nombre de particules de virus infectieuses. Exemple 2 : Effet de F. prausnitzii sur l’infection par le virus de la grippe (IAV H3N2) A. Matériels et Méthodes A.1. Protocole de traitement Des souris mâles C57BL/6J âgées de 8 semaines obtenus auprès de Janvier (Le Genest-St-Isle, France) ont été utilisés pour l’expérience. Les animaux ont été séparés en trois groupes. Un premier groupe de souris (n=5) n’a reçu que l’excipient (PBS-glycérol 16%) tout au long de la procédure et n’a pas été infecté (contrôle MOCK). Un second groupe (n=8) a reçu l’excipient (PBS-glycérol 16%) et a été inoculé après 5 jours de traitement avec le virus IAV (H3N2 Souche Scotland/20/74), par injection intranasale d’une dose de 50 PFU de virus par souris. Un troisième groupe de souris (n=10) a été traité par administration orale (intragastrique) de F. prausnitzii A2.165 à raison d’une quantité quotidienne de F. prausnitzii de 5 x 109 unités formant colonies (UFCs) en tampon PBS-glycérol 16%, les 5 jours précédents l’infection. Les souris ont été infectées par le virus H3N2 (Souche Scotland/20/74) par injection intranasale d’une dose de 50 PFU du virus. Le traitement par F. prausnitzii a été poursuivi pendant les 7 jours suivant l’infection, jusqu’au sacrifice. Le poids a été suivi quotidiennement après l’infection.
A.2. Protocoles de mesure de la charge virale L’évaluation de la charge virale du virus IAV a été réalisée à partir d’échantillons de poumon prélevés sur les animaux le jour de leur sacrifice. La mesure du nombre de copies du génome du virus IAV a été effectuée selon la méthode par qRT-PCR spécifi ue (méthode Taqman). L’ARN a été extrait des poumons par broyage en tampon RA1 (Macherey Nagel) contenant 1% de β-mercaptoethanol. L’ARN a été rétrotranscrit en cDNA par une reverse transcription spécifique à l’aide d’amorces reconnaissant la région M1 du virus IAV (5ʹ-TCT AAC CGA GGT CGA AAC GTA-3ʹ - SEQ ID NO. 4). ) et de la reverse transcriptase SuperScript® II (Invitrogen). La PCR est réalisée à l’aide du TaqMan Universal PCR Master Mix (Applied Biosystems) et d’amorces spécifique de la région M1 de IAV (sense: 5ʹ- AAG ACC AAT CCT GTC ACC TCT GA-3 – SEQ ID NO. 5ʹ; anti-sense: 5ʹ-CAA AGC GTC TAC GCT GCA GTC C-3ʹ - SEQ ID NO. 6), et d’une sonde spécifique TaqMan (marquée FAM, TAMRA (5ʹ-TTT GTG TTC ACG CTC ACC GTG CC-3ʹ - SEQ ID NO. 7). L’amplification a été réalisée sur le Quantstudio 5 (Applied Biosystems). Le nombre de copies a été évalué à l’aide d’une gamme de plasmide contenant le gène d’intérêt. A.3. Protocole de mesure d’expression génique L’expression des différents gènes a été réalisée à partir d’échantillons de poumon prélevés sur les animaux le jour de leur sacrifice. L’expression des gènes a été effectuée selon la méthode par qRT-PCR spécifique (méthode Sybergreen). L’ARN a été extrait des poumons par broyage en tampon RA1 (Macherey Nagel) contenant 1% de β- mercaptoethanol. L’ARN a été rétrotranscrit en cDNA à l’aide du kit High capacity RNA- to-cDNA kit (Applied Biosystems). La qPCR a été réalisée à l’aide du Power SYBR green PCR master Mix (Applied Biosystems) et de sondes spécifiques de chaque gène) et l’amplification est réalisée sur le Quantstudio 5 (Applied Biosystems). L’expression a été rapportée à celle d’un gène de ménage (Gapdh) et comparée (Expression relative à l’expression obtenue chez les souris contrôle non infectées. C. Résultats C1. Impact de la souche F. prausnitzii A2-165
L’impact de la souche de référence F. prausnitzii A2-165 a tout d’abord été évalué. Les résultats sont présentés dans chacune des figures 3, 4, 5 et 6 et représentent la moyenne de 4 expériences séparées. La Figure 3 montre la perte de poids induite par l’infection virale, soit en cinétique après l’infection (Fig. 3A) ou à J7 post-infection (Fig. 3B). Les souris infectées perdent progressivement du poids pour atteindre une perte de poids significative par rapport aux animaux non infectés (p< 0.001). Une diminution significative de la perte de poids (p < 0.01) est observée chez les animaux traités avec F. prausnitzii A2-165, par comparaison aux animaux qui n’ont pas reçus F. prausnitzii. La Figure 4 montre la charge virale évaluée en nombre de copies du génome de IAV par qRT-PCR spécifique (Taqman). Les données sont montrées en valeur linéaire (Fig. 4A) ou logarithmique (Fig. 4B). Comme attendu, la charge virale est significative chez les souris infectées (p < 0.0001). Les animaux qui ont été traités avec F. prausnitzii A2-165 présentent une baisse très significative (p< 0.001) de la charge virale par comparaison aux animaux qui n’ont pas reçus de F. prausnitzii. La Figure 5 montre le score clinique évalué par analyses histologiques sur des coupes de poumons colorées par l’hématoxyline et à l'éosine (H&E). Cette analyse montre une baisse significative (p< 0.05) des scores totaux (Fig. 5A), majoritairement dus à une baisse significative (p< 0.05) du pourcentage de lésions pulmonaires (Fig 5B), ainsi qu’une baisse significative du score d’inflammation vasculaire (p=0.09) (Fig 5C), chez les souris traitées par la souche F. prausnitzii A2-165. La Figure 6 montre l’expression des gènes codant pour l’Interféron gamma (Ifng) et des gènes induits par l’interféron gamma (Mx1 et Isg15) évaluée par qRT-PCR. Cette analyse montre que le traitement par F. prausnitzii A2-165 limite l’expression de ces gènes, induit par l’infection virale, ce qui est en corrélation avec la diminution de la charge virale. La Figure 7 montre l’expression de gènes pro-inflammatoires codant deux chimiokines impliquées dans le recrutement de cellules inflammatoires (MCP1/ CCL2 et CXCL2). Cette analyse montre que le traitement par F. prausnitzii A2-165 limite
significativement l’expression de ces gènes, indiquant que le traitement limite l’inflammation au niveau pulmonaire. C2. Impact de l’inactivation de la souche F. prausnitzii A2-165 Dans un deuxième temps, l’impact de la souche de référence F. prausnitzii A2- 165 a été comparé à celui de la même souche pasteurisée (traitement de 30 minutes à 100°C). Les résultats sont présentés dans chacune des figures 7, 8 et 9 et représentent la moyenne de 2 expériences séparées. La Figure 8 montre la perte de poids induite par l’infection virale, soit en cinétique après l’infection (Fig. 8A) ou à J7 post-infection (Fig. 8B). Les souris infectées perdent progressivement du poids pour atteindre une perte de poids significative par rapport aux animaux non infectés (p< 0.0001). Une diminution similaire de la perte de poids est observée chez les animaux traités avec la souche F. prausnitzii A2-165 vivante ou inactivée, par comparaison aux animaux qui n’ont pas reçus F. prausnitzii, cependant l’effet n’est pas significatif (p=NS). La Figure 9 montre la charge virale évaluée en nombre de copies du génome de IAV par qRT-PCR spécifique (Taqman). Les données sont montrées en valeur linéaire (Fig. 9A) ou logarithmique (Fig. 9B). Comme attendu, la charge virale est significative chez les souris infectées (p < 0.0001). Les animaux qui ont été traités avec la souche F. prausnitzii, A2-165 vivante présentent une baisse significative (p< 0.01) de la charge virale par comparaison aux animaux qui n’ont pas reçus de F. prausnitzii. Une diminution similaire est observée avec la souche A2-165 pasteurisée. C3. Impact de la souche F. prausnitzii I-4574 L’impact d’une autre souche de F. prausnitzii, la souche I-4574 provenant de la collection de Micalis, a été évaluée. Les résultats sont présentés dans chacune des Figures 10, 11, 12 et 13. La Figure 10 montre la perte de poids induite par l’infection virale, soit en cinétique après l’infection (Fig.10A) ou à J7 post-infection (Fig.10B). Les souris infectées perdent progressivement du poids pour atteindre une perte de poids significative par rapport aux animaux non infectés (p< 0.001). Une diminution similaire de la perte de poids est
observée chez les animaux traités avec les deux souche F. prausnitzii A2-165 et I-4574, administrées vivantes, par comparaison aux animaux qui n’ont pas reçus F. prausnitzii. La Figure 11 montre la charge virale évaluée en nombre de copies du génome de IAV par qRT-PCR spécifique (Taqman). Les données sont montrées en valeur linéaire (Fig. 11A) ou logarithmique (Fig. 11B). Comme attendu, la charge virale est significative chez les souris infectées (p < 0.01). Les animaux qui ont été traités avec la souche F. prausnitzii I-4574 présentent une baisse significative (p< 0.01) de la charge virale par comparaison aux animaux qui n’ont pas reçus de F. prausnitzii. La Figure 12 montre l’expression des gènes codant pour l’Interféron gamma (Ifng) et beta (Ifnb) et le gène induits par l’interféron gamma (Isg15) évaluée par qRT-PCR. Cette analyse montre que le traitement par F. prausnitzii I-4574 diminue significativement l’expression des interférons et, à la limite de la significativité, l’expression d’Isg15 (p=0.09) induit par l’infection virale, ce qui est en corrélation avec la diminution de la charge virale. La Figure 13 montre l’expression de gènes pro-inflammatoires (Il6, Mcp1/Ccl2, Cxcl2) évaluée par qRT-PCR. Cette analyse montre que le traitement par F. prausnitzii I- 4574 diminue significativement l’expression de ces gènes (p< 0.05-0.01), seule l’expression de Cxcl2 étant à la limite de significativité (p=0.09).
Description Title: Use of Faecalibacterium to treat respiratory virus infection Technical field The present invention relates to the field of the treatment of respiratory virus infections. PRIOR ART Respiratory viruses include many viruses which infect cells of the respiratory tract, which cause respiratory disease symptoms and which are transmitted primarily through the respiratory secretions of infected individuals. Respiratory viruses are the most frequent causative agents that cause pathologies in humans and animals. In humans and animals, respiratory virus infections have a global impact on morbidity and mortality. Thus, a plurality of respiratory viruses commonly circulate among men of all ages with high efficiency of human-to-human transmission. These are in particular the following viruses: (i) human respiratory syncytial virus (HRSV), (ii) human parainfluenza virus (HPIV), (iii) human respiratory virus (HRV), (iv) Aleutian disease (ADV), (v) human coronavirus (HCoV), (vi) severe acute respiratory syndrome coronavirus (SARS-CoV 1 and 2), (vii) human metapneumovirus (HPMV), (viii) human bocavirus (HBoV) or (ix) influenza virus (IAV) (Boncristiani et al., 2009, Encyclopedia of microbiology: 500-518; doi: 10.1016/B978-01237944-5.00314-X). Regarding the immune response against viral infection, there is a growing body of evidence indicating the critical role of the gut microbiota in the homeostasis of the immune system, which encompasses the immune response against viruses, including including against respiratory viruses. Within the intestinal microbial communities, Bacteroidetes and Firmicutes are predominant. The predominant microbial communities in the intestine and in the lungs are similar. The gut microbiota affects pulmonary immunity due to an established dialogue between the gut microbiota and the gut and lungs, which is sometimes referred to as the gut-lung axis. This gut-lung axis, which is bidirectional, encompasses the passage of endotoxins, metabolites and hormones in the circulating blood, and connects the intestinal niche to the lungs. It is known that the gut microbiota can be significantly altered during a variety of respiratory disorders caused by a wide range of airborne pathogens, particularly pathogenic viruses (Dumas et al., 2018, Cell Microbiol, 20 :e12966). In particular, a reduction in the diversity of the intestinal microbiota has been shown in subjects infected with various respiratory viruses, this reduction in the diversity of the microbiota being associated with increased mortality. This increased mortality observed in respiratory virus infections has been associated with a failure of the immune response characterized by the increased production of interferon gamma, IL-6 and CCL2, and by a reduced number of Treg cells in intestine and lungs (Grayson et al., 2018, Front Immunol, Vol. 9: 1587). Similarly, mouse models of influenza virus and respiratory syncitial virus (RSV) altered the diversity of the gut microbiota, with a decrease in the abundance of Firmicutes phyla (Rangelova et al., 2019, Ann Surg doi:10.1097 SLA.0000000000003301 [Epub ahead of print]; Zhang et al., 2020, Frontiers in Microbiology, Vol. 11: Art. 301:1-14). It was observed by He et al. (2002, Canad J Infect Dis, Vol. 2021: 1-10) a low abundance of F. prausnitzii, particularly in people infected with the COVID 19 virus. These authors believe that F. prausnitzii would have a potential ability to reduce inflammation and to prevent the occurrence of gastrointestinal co-morbidities, particularly in patients infected with the COVID-19 virus. These authors report the existence of studies which would have shown a correlation between a low abundance of F. prausnitzii and an increased incidence of metabolic inflammatory diseases. It is thus proposed that the anti-inflammatory effects of F. prausnitzii could lead to the prevention and alleviation of symptoms caused by infection with the COVID-19 virus, at least in combination with medicinal agents. Patent documents US 2018/0264053 and US 2021/0077541 propose compositions comprising various combinations of bacteria for the purpose of preventing or treating inflammatory diseases. The PCT application published under the number WO 2021/146523 describes solid dosage forms allowing an improved oral release of bacteria and agents of bacterial origin, which can be used in particular, because of their anti-inflammatory properties, in the treatment of viral infections. Various mechanisms having the effect of reducing an immune response are common to the various respiratory viruses, which includes viruses inducing severe acute respiratory distress syndrome (such as the MERS-CoV and SARS-CoVs viruses) or even other RNA viruses such as respiratory syncitial virus (RSV), parainfuenza virus 3 (HIPV3) and Influenza virus (IAV) (Blanco-Melo et al., 2020, Cell, Vol. 181: 1036-1045). Preventive treatments against infection by various respiratory viruses are known, mainly in the form of vaccines. Given the rate of hospitalizations due to infection by respiratory viruses, and also the large number of deaths found in subjects infected by these viruses, there is a need for the identification of therapeutic treatments, alternative or improved compared to treatments known therapies. Moreover, there does not currently seem to be any effective therapeutic treatment against some of these respiratory viruses, in particular for the treatment of an infection by a SARS-CoV-2 virus. Also, as with the influenza virus, antiviral agents must be administered soon after infection to be effective. This constraint makes it difficult to identify suitable molecules. Many trials have aimed to identify, among the many known antiviral agents, active agents against SARS-CoV-2, but without success until today. According to other strategies, in the absence of active agents directly on the viral particles, certain agents have been used for the purpose of reducing certain deleterious physiological consequences of an infection by the SARS-CoV-2 virus, such as (i ) dexamethasone, for the purpose of modulating lung damage due to inflammation and thus reduce the progression of respiratory distress syndrome and the occurrence of death, (ii) immunosuppressive antibodies such as tocilizumab or sarimumab, or even (iii) kinase inhibitors, for the purpose of controlling downstream inflammation. There remains a need for prophylactic or therapeutic treatments for infections by a respiratory virus, alternative or improved compared to the known treatments. Summary of the Invention This disclosure relates to bacteria of the genus Faecalibacterium, which includes bacteria of the species Faecalibacterium prausnitzii and Faecalibacterium duncaniae, for their use for the prevention or treatment of an infection of a subject, whether human or animal, by a respiratory virus, preferably by a human respiratory virus. Thus, the present description relates to bacteria chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae for their use for the prevention or treatment of an infection of a subject, that he either human or animal, by a respiratory virus preferably by a human respiratory virus. In certain embodiments, these bacteria of the genus Faecalibacterium are useful for the prevention or treatment of infection of a subject by a respiratory virus causing severe acute respiratory distress syndrome, which includes infection by a respiratory virus of human preference. In certain embodiments, said bacteria of the genus Faecalibacterium belong to strain A2-165. In certain other embodiments, said bacteria of the Faecalibacterium genus belong to strain I-4574, deposited at the CNCM (National Collection of Microorganism Cultures) on December 7, 2011 by INRA (National Institute for Agronomic Research), which has since been called INRAE (National Research Institute for Agriculture, Food and the Environment). In certain embodiments, said respiratory virus is chosen from (i) a human respiratory syncitial virus (HRSV), (ii) a human parainfluenza virus (HPIV), (iii) a human rhinovirus (HRV), (iv) a virus Aleutian disease (ADV), (v) human coronavirus (HCoV), (vi) human metapneumovirus (HPMV), (vii) human bocavirus (HBoV), (viii) human parainfluenza virus (HIPV) (ix ) human influenza virus (IAV), (x) rotaviruses, (xi) caliciviruses, (xii) toroviruses, (xiii) adenoviruses, (xiv) BHV and ADV herpesviruses and (xv) pestiviruses . In certain embodiments, said virus is a SARS-CoV respiratory virus, preferably a SARS-CoV-2 respiratory virus. In certain other embodiments, said virus is a human influenza virus (IAV). In certain embodiments, these bacteria of the genus Faecalibacterium are useful for reducing the subject's viral load of said respiratory virus, preferably the subject's lung load of said respiratory virus. In certain embodiments, said bacteria, said bacteria of the Faecalibacterium genus are included in a composition, in association with at least one physiologically acceptable excipient. In certain embodiments, said Faecalibacterium bacteria are included in a composition in a form suitable for nasal, oral or rectal administration. In certain embodiments, said oral composition is selected from the group consisting of a food product, a beverage, a pharmaceutical product, a nutraceutical, a food additive, a food supplement and a dairy product. In certain embodiments, said bacteria of the genus Faecalibacterium are included in a composition in a form suitable for administration of 10 3 to 10 11 colony forming units. Brief description of the drawings Figure 1 represents the viral load of SARS-CoV-2 virus in hamsters, four days after infection. On the ordinate, the viral load expressed as the number of copies of the SARS-CoV-2 virus genome per µL. On the abscissa, the groups of animals, from right to left (i) control animals infected with SARS-CoV-2 not treated with F. prausnitzii and (ii) animals infected with SARS-CoV-2 and treated with F. prausnitzii. The difference is statistically significant with a P value of 0.0006. Figure 2 represents the viral load of SARS-CoV-2 virus in hamsters, four days after infection. On the ordinate, the viral load expressed as the number of SARS-CoV-2 virus particles per mL. On the abscissa, the groups of animals, from right to left (i) control animals infected with SARS-CoV-2 not treated with F. prausnitzii and (ii) animals infected with SARS-CoV-2 and treated with F. prausnitzii. The difference is statistically significant with a P value of 0.01. Figure 3 represents the weight loss induced by viral infection by IAV in 8-week-old male C57BL/6J mice, either in kinetics after infection (Fig. 3A) or at D7 post-infection (Fig. 3B) . The results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F. prausnitzii according to the invention (group IAV F. prausnitzii A2.165). Figure 3A: Abscissa: days. Y-axis: % of the initial weight of the mice. Figure 3B: Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2.165 group. Y-axis: % weight loss of mice. FIG. 4 represents the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 4A) or logarithmic (Fig. 4B) value. The results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F. prausnitzii according to the invention (group IAV F. prausnitzii A2.165). Figure 4A: Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2.165 group. Y-axis: Copy number of IAV (M1 gene). Figure 4B: Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2.165 group. Y-axis: Number of copies of IAV (M1 gene) in Log 10 . ***: p<0.001; ****: p<0.0001 FIG. 5 represents the clinical score evaluated by histological analyzes on lung sections stained with hematoxylin and eosin (H&E). This analysis shows a significant drop (*: p< 0.05) in total scores (Fig. 5A), mainly due to a significant drop (*: p< 0.05) in the percentage of lung lesions (Fig 5B), as well as a drop significant vascular inflammation score (p=0.09) (FIG. 5C), in mice treated with the F. prausnitzii A2-165 strain (IAV F. prausnitzii A2.165 group). The same groups as previously indicated are represented. Abscissa for Figures 5A, 5B and 5C: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2.165 group. Ordered for 5A: total scores. Ordered for 5B: percentage of lesions. Ordered for 5C: Scores. Figure 6 represents the expression of genes coding for Interferon beta (Ifnb - Figure 6A) and genes induced by interferon gamma (Mx1 and Isg15 - respectively Figures 6B and 6C), genes linked to viral infection, assessed by qRT-PCR. The same groups as previously indicated are represented. Abscissa for Figures 6A, 6B and 6C: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2-165 group. Ordinate for 6A: Relative expression in Ifnb. Ordered for 6B: Relative expression in Mx1. Ordered for 6C: Relative expression in Isg15. Figure 7 shows the expression of pro-inflammatory genes encoding two chemokines involved in the recruitment of inflammatory cells: MCP1/CCL2 (Figure 7A) and CXCL2 (Figure 7B), assessed by qRT-PCR. The same groups as previously indicated are represented. Abscissa for Figures 7A and 7B: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii A2-165 group. Ordered for 7A: Relative expression in Mcp1/Ccl2. Ordered for 7B: Relative expression in Cxcl2. Figure 8 represents the weight loss induced by viral infection by IAV in 8-week-old male C57BL/6J mice, either in kinetics after infection (Fig. 8A) or at D7 post-infection (Fig. 8B) . The results obtained in four groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group), a group infected with IAV and having received a treatment of live F. prausnitzii A2-165 according to the invention (live IAV F. prausnitzii A2-165 group) and a group infected with IAV and having received a treatment of inactivated (pasteurized) F. prausnitzii A2-165 according to the invention (group IAV F. prausnitzii A2-165 pasteurized). Figure 8A: Abscissa: days post infection. Y-axis: % of the initial weight of the mice. Figure 8B: Abscissa: from left to right: Uninfected group, IAV infected group, live IAV F. prausnitzii A2-165 group and IAV infected group, pasteurized IAV F. prausnitzii A2-165 group. Y-axis: % weight loss of mice. FIG. 9 represents the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 9A) or logarithmic (Fig. 9B) values. (****=p<0.001;**=p<0.01) of viral load compared to animals which did not receive F. prausnitzii. The results obtained in four groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group), a group infected with IAV and having received a treatment of live F. prausnitzii A2-165 according to the invention (group IAV F. prausnitzii A2.165 live) and a group infected with IAV and having received a treatment of pasteurized F. prausnitzii A2-165 according to the invention (group IAV F. prausnitzii A2.165 pasteurized). Figure 9A: Abscissa: from left to right: Uninfected group, IAV infected group, live IAV F. prausnitzii A2.165 group and pasteurized IAV F. prausnitzii A2.165 group. Y-axis: Copy number of IAV (M1 gene). Figure 9B: Abscissa: from left to right: Uninfected group, IAV infected group, live IAV F. prausnitzii A2.165 group and pasteurized IAV F. prausnitzii A2.165 group. Y-axis: Number of copies of IAV (M1 gene) in Log 10 . Figure 10 represents the weight loss induced by viral infection by IAV in 8-week-old male C57BL/6J mice, either in kinetics after infection (Fig. 10A) or at D7 post-infection (Fig. 10B) . The results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F. prausnitzii I-4574 according to the invention (group IAV F. prausnitzii I-4574). Figure 10A: Abscissa: days post infection. Y-axis: % of the initial weight of the mice. Figure 10B: Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii I-4574 group. Y-axis: % weight loss of mice. FIG. 11 represents the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 11A) or logarithmic (Fig. 11B) values. (**=p<0.01) of viral load compared to animals which did not receive F. prausnitzii. The results obtained in three groups of animals are represented: a control group not infected with the virus (Uninfected group), a control group infected with IAV but not treated (IAV infected group) and a group infected with IAV and having received a treatment of F. prausnitzii I-4574 according to the invention (group IAV F. prausnitzii I-4574). Figures 11A and 11B: Abscissa: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii I-4574 group. Y-axis Figure 11A: Copy number of IAV (M1 gene). Y-axis Figure 11B: Number of copies of IAV (M1 gene) in Log 10 . Figure 12 represents the expression of the genes coding for Interferon gamma (Ifng - Figure 12A) and Interferon beta (Ifnb - Figure 12B) and of the gene induced by interferon gamma (Isg15 Figures 12C), gene linked to viral infection, assessed by qRT-PCR. The same groups as previously indicated are represented. Abscissa for Figures 12A, 12B and 12C: from left to right: Uninfected group, IAV infected group and IAV F. prausnitzii I-4574 group. Ordered for 12A: Relative expression in Ifng. Ordered for 12B: Relative expression in Ifnb. Ordered for 12C: Relative expression in Isg15. Figure 13 shows the expression of pro-inflammatory genes: Il6 (Figure 13A), MCP1/CCL2 (Figure 13B) and CXCL2 (Figure 13C), assessed by qRT-PCR. The same groups as previously indicated are represented. Abscissa for Figures 13A, 13B and 13C: from left to right: Uninfected group, IAV infected group and IAV F group. prausnitzii I-4574. Ordered for 13A: Relative expression in Mcp1/Ccl2. Ordered for 13B: Relative expression in Mcp1/Ccl2. Ordered for 13C: Relative expression in Cxcl2. Detailed description The inventors have shown that the supply of bacteria of the genus Faecalibacterium, in particular bacteria of the species Faecalibacterium prausnitzii (also called F. prausnitzii in the present description) to subjects infected with a respiratory virus, in particular subjects infected with a SARS-CoV-2 virus and in subjects infected with the influenza virus, causes a very significant reduction in the viral load of the subject, in particular a very significant reduction in the pulmonary viral load of the subject. In addition, it is shown that an intake of bacteria of the genus Faecalibacterium, in particular of bacteria of the species F. prausnitzii, prior to infection by a respiratory virus, in particular prior to infection by a SARS-CoV- 2, allows a reduced viral load of the subject who is subsequently infected, in particular allows a reduced pulmonary viral load of the subject who is subsequently infected, in comparison with a subject infected under the same conditions with said respiratory virus but who has not received said contribution of bacteria of the genus Faecalibacterium. The reduced viral load that is observed is illustrated both (i) by a decrease in the number of copies of the viral genome and (ii) by a decrease in the number of viral particles, particularly in the lungs. The inventors have also shown that the supply of bacteria of the genus Faecalibacterium, in particular bacteria of the species F. prausnitzii, makes it possible to reduce, in a subject, the presence or the extent of pulmonary lesions caused by an infection of the subject by a respiratory virus, such as SARS-CoV-2 or Influenza. It is also shown in the examples that the supply of bacteria of the genus Faecalibacterium, in particular bacteria of the species F. prausnitzii, makes it possible to reduce, in a subject, the vascular inflammation caused by an infection of the subject by a virus respiratory, such as SARS-CoV-2 or Influenza. The inventors have also shown that the intake of bacteria of the genus Faecalibacterium, in particular bacteria of the species F. prausnitzii, especially in subjects infected with a respiratory virus such as SARS-CoV-2 or Influenza, induces an increase in level of expression of genes involved in the anti-viral response of the host, such as the following genes: (i) the Ifng gene encoding interferon gamma, (ii) the Ifnb gene encoding interferon beta, (iii) the IfnI3 gene encoding interferon lambda 3, (iv) the Mx1 gene encoding the Mx1 protein binding to GTP and which is induced by interferon, (v) the Isg15 gene which is stimulated by interferon or (vi) the STAT1 gene which is activated by type 1 interferons. To the applicant's knowledge, the direct effect on a viral infection of bacteria of the genus Faecalibacterium, and in particular the effect of these bacteria on the viral load, and even more particularly on the viral load of a respiratory virus, nor on their effects on lesions, in particular on the lungs, of an infection by a respiratory virus, have never been shown in the state of the art. The present invention relates to bacteria of the genus Faecalibacterium for their use in the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human. The bacteria of the genus Faecalibacterium can be chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae. The present invention relates to bacteria of the genus Faecalibacterium for their use, as an antiviral agent, for the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus preferably human. The bacteria of the genus Faecalibacterium can be chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae. It relates to the use of bacteria of the genus Faecalibacterium for the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human. It relates to the use of bacteria of the genus Faecalibacterium for the prevention or treatment, as an antiviral agent, of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus preferably human. It relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for the prevention or treatment of an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human . It relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for the prevention or treatment, as an antiviral agent, of an infection of a subject by a respiratory virus, which includes a infection with a respiratory virus, preferably human. It relates to a method for preventing or treating an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human, comprising a step during which it is brought to the subject bacteria of the genus Faecalibacterium. It relates to a method for preventing or treating an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human, comprising a step during which it is brought to the subject bacteria of the genus Faecalibacterium in as an antiviral agent. The present invention relates to bacteria of the genus Faecalibacterium for reducing damage to the body, in particular for reducing lung damage, caused by infection of a subject with a respiratory virus, which preferably includes infection with a respiratory virus human. It relates to the use of bacteria of the genus Faecalibacterium for reducing the lesions of the organism, in particular for reducing the pulmonary lesions, caused by an infection of a subject by a respiratory virus, which includes an infection by a virus preferably human respiratory. It relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for reducing the lesions of the organism, in particular for reducing the lesions of the lungs, caused by an infection of a subject by a respiratory virus, this which includes infection with a respiratory virus, preferably human. It relates to a method for reducing damage to the body, in particular for reducing lung damage, caused by an infection of a subject by a respiratory virus, which includes an infection by a respiratory virus, preferably human, comprising a step during which it is brought about bacteria of the genus Faecalibacterium. By prevention or treatment of "an infection of a subject" by a respiratory virus, is meant according to the present description a prophylactic or therapeutic effect on the level of infection by a respiratory virus when the infection occurs, And more particularly a prophylactic or therapeutic effect on the level of viral load of the subject, after the occurrence of an infection by a virus, here a respiratory virus. By “subject”, according to the description, is meant a subject chosen from among humans and animals. Animals include non-human mammals that belong to the group of production, livestock or companion animals, such as a canid, a felid or an equine. Most preferably, a subject is a human being. By "human virus" is meant a virus having the capacity to infect a human subject. By “non-human virus”, is meant a virus having the capacity to infect a non-human subject, that is to say an animal. It is specified that some of the viruses of interest for the present description are both human viruses and non-human viruses, such as for example MERS-CoV. By "antiviral agent" is meant an agent capable of reducing the viral load of a subject, which includes that the antiviral agent is capable of (i) reducing the number of copies of the viral genome and/or (ii) reducing the number of viral particles in the infected subject's body, which includes in the infected subject's lung tissue. F. prausnitzii is a major member of the phylum Firmicutes and is among the most abundant commensal bacteria in the microbiota of the healthy human large intestine. F. prausnitzii is, in particular, known to be one of the most abundant butyrate-producing bacteria in the human digestive tract, the short-chain fatty acid butyrate being very important in the physiology of the intestine, systemic functions and beneficial effects on human health (Macfarlane and Macfarlane (2011), J. Clin. Gastroenterol. 45 Suppl: S120-7). Very recently, changes in the classification of bacteria of the genus Faecalibacterium have been proposed, the proposed new classification being based on the characteristics of the bacterial genome (Sakamoto et al., 2022, International Journal of Systematic and Evolutionary Microbiology, Vol. 72: 005379 – Doi: 10.1099//jsem.0.005379). In this context, for example, it is proposed that the bacterium Faecalibacterium prausnitzii A2-165 be classified as Faecalibacterium duncaniae. Within the meaning of the present description, the bacteria F. prausnitzii include the bacteria which were classified as belonging to the species F. prausnitzii on the date of September 10, 2021. The bacteria of the genus Faecalibacterium, in particular the bacteria of the species F prausnitzii, include those referenced in the PCT application published under the number WO 2016/075294, which includes the bacteria deposited according to the Budapest Treaty in the Microorganism Cultures Collection of the Institut Pasteur under the accession numbers I- 4542, I-4544, I-4540, I-4574, I-4543, I-4575, I-4573, I-4644 and I-4546. Bacteria of the genus Faecalibacterium, in particular bacteria of the species F prausnitzii also include strains deposited with the American Type Culture Collection (ATCC) under ATCC accession number 27768. Bacteria of the genus Faecalibacterium may be bacteria of the A2-165 strain deposited at the German Collection for Cell Cultures and Microorganisms (DMSZ) under the accession number DSM 17677. The bacteria of the genus Faecalibacterium can be live bacteria, inactivated bacteria or dead bacteria. In certain embodiments, the bacteria of the genus Faecalibacterium are live bacteria. By "live bacteria" is meant according to the present description, bacteria capable of multiplying, under appropriate conditions. In certain other embodiments, the bacteria of the genus Faecalibacterium are inactivated bacteria or dead bacteria. According to the present description, "inactivated" bacteria are not capable, at least transiently, which includes permanently, of forming colonies in culture, under appropriate culture conditions. According to the present description, "dead" bacteria are bacteria which are no longer, permanently and definitively, capable of forming colonies in culture, under appropriate culture conditions. Inactivated bacteria or dead bacteria may have intact or at least partially ruptured membrane walls. Inactivated bacteria can be prepared by exposing the bacterial cells to irradiation, for example by ionizing radiation, by inactivation heat, by acid or base inactivation, by inactivation by exposure to air or oxygen, or by freeze-drying. Each of these methods of inactivating bacteria is well known to those skilled in the art. Inactivation by irradiation can be carried out by exposing the bacteria to gamma radiation, to X-rays, or even by exposure to UV radiation. Bacteria inactivated by freeze-drying can be reactivated and recultured. Thermal inactivation can be carried out by incubating bacteria of the genus Faecalibacterium for a prolonged period, for example at least two hours, at 170° C. Thermal inactivation can also be carried out by autoclaving, by subjecting the bacteria of the genus Faecalibacterium to a temperature of 121°C for a period of at least 20 minutes and at an atmospheric pressure of 2 bar. Also encompassed are thermal inactivation processes such as pasteurization or tyndallization. Alternatively, heat inactivation can be achieved by subjecting bacteria of the genus Faecalibacterium to freezing temperature for an extended period of time. Inactivation by pH can be achieved by incubating bacteria of the genus Faecalibacterium for an extended period of time in low or high pH, for example for 30 min at pH 2. Inactivation by exposure to air can be achieved because bacteria of the genus Faecalibacterium, in particular Faecalibacterium prausnitzii, are extremely oxygen-sensitive (EOS) organisms. The process can be carried out by incubating the bacterium in question for a certain time in an atmosphere of air. The present description also encompasses not only the use of bacteria of the genus Faecalibacterium, but also the use of a bacterial extract or a bacterial lysate obtained from bacteria of the genus Faecalibacterium, for each of the uses of bacteria of the genus Faecalibacterium which is described in this description. An extract or lysate which is suitable for the uses specified in the present description can be prepared from the bacteria of the genus Faecalibacterium, at the end of the growth phase. A bacterial strain which is suitable for a use specified in this description can be used in the form of a lysate. Within the meaning of the invention, a "lysate" commonly designates a material obtained after destruction or dissolution of biological cells by a phenomenon known as cell lysis, thus giving rise to the release of the intracellular biological constituents naturally contained in the cells of the bacterium under consideration. In the context of the present description, the term “lysate” is used without preference to designate the entire lysate obtained by lysis of the bacterium under consideration or only a fraction thereof. The lysate used is therefore totally or partially formed of the intracellular biological constituents and of the constituents of the cell walls and membranes of the bacteria. Within the meaning of the present description, the term “fraction” designates more particularly fragments of said bacterium. In a particular embodiment, a lysate according to the present description can be the whole lysate obtained by lysis of the bacterial strains considered. This cell lysis can be carried out by various known techniques, such as osmotic shock, thermal shock, by exposure to ultrasound, or alternatively under mechanical stress of the centrifugation type. In particular, a lysate according to the present description can be obtained by ultrasonic disintegration of a medium comprising bacteria of the genus Faecalibacterium, in particular bacteria of the species F. pausnitzii or of the species F. duncaniae, in suspension in order to to release cytoplasmic fractions, cell wall fragments and metabolic products. All components in their natural distribution are then stabilized in a weakly acidic aqueous solution. It is specified that the techniques above, illustrated for bacteria of the genus Faecalibacterium, can also be used to kill or inactivate bacteria of other species, likely to be combined with Faecalibacterium, in particular with F. prausnitzii or F. duncaniae, in a composition of interest specified in the present description. The respiratory viruses are preferably chosen from respiratory viruses causing severe acute respiratory distress syndrome. Respiratory viruses include (i) respiratory viruses infecting human subjects and (ii) respiratory viruses infecting non-human subjects, i.e. animals and more especially non-human mammals, such as for example, without being limiting, cattle, sheep, pigs, canines, felines or even horses. The respiratory viruses, including human respiratory viruses, can be chosen, by way of non-limiting examples, from (i) a human respiratory syncytial virus (HRSV), (ii) a human parainfluenza virus (HPIV), (iii) human rhinovirus (HRV), (iv) Aleutian disease virus (ADV), (v) human coronavirus (HcoV), (vi) human metapneumovirus (HPMV), (vii) human bocavirus (HboV), (viii) human parainfluenza virus (HIPV), (ix) human influenza virus (IAV), (x) rotaviruses, (xi) caliciviruses, (xii) toroviruses, (xiii) adenoviruses, ( xiv) BHV and ADV herpesviruses and (xv) pestiviruses. The rotaviruses can be chosen from the RVA, RGB, RVC and RVH viruses. The calicivirus can be chosen from novoviruses and sapoviruses. The pestiviruses can be chosen from the BVDV and CSFV viruses. The coronaviruses are selected from (i) coronaviruses infecting human subjects and (ii) coronaviruses infecting non-human subjects, which includes non-human mammals. Those skilled in the art can refer in particular to the review article by Khbou et al. (2021, Vet Med Sci, Vol. 7: 322-347). The coronaviruses infecting non-human subjects can be chosen, by way of non-limiting examples, from (i) bovine coronaviruses, such as bovine coronavirus (BcoV), (ii) coroonaviruses infecting buffaloes, such as Bubaline coronavirus (BuCoV), (iii) coronaviruses infecting camels, such as Middle East respiratory syndrome coronavirus (MERS-CoV), (iv) coronaviruses infecting horses, such as Equine coronavirus (EcoV), (v) coronaviruses infecting rabbits, such as Rabbit coronavirus (RbCoV), (vi) coronaviruses infecting porcines, such as Porcine hemagglutinating encephalomyelitis virus (PHEV), Transmissible gastroenteritis virus (TGEV), Porcine respiratory coronavirus (PRCV), Swine acute diarrhoea syndrome coronavirus (SADS-CoV), Porcine epidemic diarrhoea virus (PEDV) and Porcine delatocoronavirus (PDCov), (vii) coronaviruses infecting chickens, such as Infectious bronchitis virus (IBV), (viii) the coronaviruses s infecting dolphins, such as Bottlenoise whale (BdCoV), (ix) coronaviruses infecting whales, such as Beluga whale (BWCoV) and (x) coronaviruses infecting seals. The human coronaviruses are chosen in particular from (i) a Middle East respiratory syndrome coronavirus (MERS-CoV), and (ii) a coronavirus responsible for severe acute respiratory syndrome (SARS-CoV). The SARS-CoV respiratory viruses can be chosen from SARS-CoV-1 viruses and SARS-CoV-2 viruses. They are preferably SARS-CoV-2 respiratory viruses. The respiratory viruses can be chosen from Influenza viruses, preferably a human Influenza virus. The Influenza virus can be a virus of one of the types A, B or C and is preferentially a type A Influenza virus (also called “IAV” in the present description). It may be an Influenza virus of type A, of a subtype chosen from A(H1N1) and A(H3N2). It may be a type B Influenza virus, of a subtype chosen from B (Victoria) and B (Yamagata). The species of respiratory viruses, preferably the species of human respiratory viruses, encompass the different strains, sometimes referred to as “variants”, of said viruses. By way of illustration, the viruses of the SARS-CoV-2 type encompass the different strains, sometimes referred to as “variants”, of these viruses. Similarly, an Influenza virus belonging to a given subtype, is classified according to a subclassification in clades (groups), then in subclades (subgroups). By way of illustration, a type A Influenza virus (IAV) can be classified in the A(H1N1) subtype, then in the 68.1 clade and finally in the 68.1.A subclade. Similarly, strains of type A Influenza virus (IAV) can be classified in the A(H3N2) subtype. The invention relates to bacteria of the genus Faecalibacterium for their use for the prevention or treatment of an infection of a subject with a respiratory virus, preferably with a human respiratory virus, to reduce the subject's viral load of said respiratory virus during the infection. The bacteria of the genus Faecalibacterium can be chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae. The invention relates to the use of bacteria of the genus Faecalibacterium for the manufacture of a medicament for the prevention or treatment of an infection of a subject by a respiratory virus, preferably by a human respiratory virus, to reduce the burden virus of the subject into said respiratory virus during the infection. The invention relates to a method for the prevention or treatment of an infection of a subject by a respiratory virus, to reduce the viral load of the subject during the infection, comprising a step of supplying said subject with bacteria of the genus Faecalibacterium. The invention also relates to a prophylactic or therapeutic method for obtaining a reduced viral load in a subject when he is infected with a respiratory virus, said method comprising a step of supplying said subject with bacteria of the genus Faecalibacterium. By “viral load” of a subject within the meaning of the present description, is meant a quantity of virus present in a tissue and/or an organ of said subject. Preferably, within the meaning of the present description, the subject's viral load consists of a quantity of virus present in the pulmonary tissue and/or in the pulmonary fluid of said subject. Within the meaning of the present description, a quantity of virus can be expressed (i) in number of copies of viral genome or (ii) in number of infectious viral particles. As is known, the number of viral genome copies can be determined according to a method comprising a step of amplification of the viral RNA, preferably according to the RT-PCR technique, as illustrated in the examples. As is known, the number of infectious viral particles can be determined using a viral particle titration method comprising a step of infecting cells sensitive to said virus. The results can be expressed in TCID50/mL, ie in the quantity of virus necessary to cause the infection of 50% of the susceptible cells. Within the meaning of the present description, the viral load of a subject is reduced when a decrease of at least 5 times, better still of at least 10 times, the reference viral load is measured, compared to a reference value . For example, a reduction in the viral load of a subject in a respiratory virus is attested when a reduction of at least 5 times the number of copies of the genome of said virus, better still of at least 10 times the number of copies of the genome of said virus is measured, relative to a reference value. Also, a reduction in the viral load of a subject in a respiratory virus is attested when a decrease of at least 5 times the number of particles of said virus, better still at least 10 times the number of particles of said virus, is measured, relative to a reference value. As illustrated in the examples, a supply of bacteria of the genus Faecalibacterium has the property, in a subject infected with a respiratory virus, in particular infected with a SARS-CoV-2 virus, of reducing the viral load by more than 10 times. , compared with a subject who did not receive a supply of bacteria of the genus Faecalibacterium, whether this viral load is expressed (i) as a number of copies of the viral genome or (ii) as a number of viral particles. Compositions The present invention also relates to a composition comprising, in a physiologically acceptable medium, at least bacteria of the genus Faecalibacterium, in particular bacteria of the species F prausnitzii or bacteria of the species F. duncaniae. Preferably, a composition according to the present description has a formulation suitable for its administration intranasally, orally or rectally. Suitable Faecalibacterium bacteria are described elsewhere in this specification. In certain embodiments of a composition according to the description, the chosen strain of Faecalibacterium, in particular of F. prausnitzii or of F. duncaniae, is used as the only bacterial strain present in the composition. In certain embodiments, a combination of several strains of Faecalibacterium, in particular of F. prausnitzii or of F. duncaniae, are the only bacterial strains present in the composition. In certain other embodiments of a composition according to the description, Faecalibacterium bacteria, in particular F. prausnitzii or F. duncaniae, are combined with bacteria from one or more other probiotic bacterial strains, which includes other commensal probiotic bacterial strains. Non-limiting examples of probiotics include strains of bacteria belonging to the following genera: Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, and three yeasts Kluyveromyces, Saccharomyces, Candida and combinations thereof. The probiotics may be chosen from the group consisting of the following bacterial species: Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei (from now on Lacticaseibacillus casei), Lactobacillus paracasei (from now on Lacticaseibacillus paracasei), Lactobacillus salivarius (now Ligilactobacillus salivarius), Lactobacillus lactis (now Lactobacillus delbrueckii subsp. Lactis), Lactobacillus rhamnosus (now Lacticaseibacillus rhamnosus), Lactobacillus johnsonii, Lactobacillus plantarum (now Lactiplantibacillus plantarum subsp. Plantarum), Lactococcus lactis, Enterococcus faecium, Sac cerevisiae, Saccharomyces boulardii or their mixtures, preferably chosen from the group consisting of Bifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longum NCC2705 (CNCM 1-2618), Bifidobacterium longum N CC490 (CNCM 1-2170), Bifidobacterium lactis NCC2818 (CNCM I-3446), Bifidobacterium breve strain A, Lactobacillus paracasei NCC2461 (CNCM 1-2116), Lactobacillus johnsonsii NCC533 (CNCM 1-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CGMCC 1.3724), Enterococcus faecium SF 68 (NCC2768; NCIMB10415), Faecalibacterium prausnitzii and their combinations. In certain embodiments, a composition according to the present description is combined, for example in a kit, with one or more other agents useful for the treatment of an infection of a subject by a SARS-CoV-2 virus. These embodiments include those in which a composition according to the present description is combined, for example in a kit, with one or more antibodies directed against a SARS-CoV-2 virus. These embodiments also encompass those in which a composition according to the present description is combined, for example in a kit, with one or more anti-viral agents. In some embodiments, the composition also includes one or more prebiotics. The term "prebiotic" is used in its conventional sense in the state of the art. Prebiotics consist of food substances that promote the growth of probiotic bacteria, including bacteria included in the microbiota. Non-limiting examples of prebiotics include: oligosaccharides optionally containing fructose, galactose, mannose; dietary fibers, in particular fermentable fibers, soy fibers; inulin; and their combinations. The preferred prebiotics are fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), isomalto-oligosaccharides (IMO), xylo-oligosaccharides (XOS), arabino-xylo-oligosaccharides (AXOS), mannan-oligosaccharides (MOS), soy oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose-oligosaccharides (PAO), malto-oligosaccharides, resistant starches, gums and/or hydrolysates thereof, pectins and/or hydrolysates thereof, or combinations thereof. In some embodiments, the composition further comprises one or more vitamins. The vitamins can be folic acid, vitamin B12 and vitamin B6, especially folic acid, and vitamin B12, especially folic acid. In some embodiments, the composition includes one or more vitamins that are fat-soluble, for example, one or more of vitamin A, vitamin D, vitamin E, and vitamin K. In some embodiments, the composition includes a or more polyphenols, such as flavanols, flavanones, flavonols, hydroxycinnamic acids and anthocyanins. In some embodiments, the composition further includes one or more minerals. The minerals can be selected from sodium, potassium, chloride, calcium, phosphate, magnesium, iron, zinc, copper, selenium, manganese, fluorine, iodine, chromium or molybdenum. Minerals are usually added in the form of salt. The minerals can be added alone or in combination. In certain embodiments, a composition according to the present description generally comprises carriers or vehicles. "Carriers" or "vehicles" refer to materials suitable for administration and include any material known in the state of the art, such as, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent or the like, which is non-toxic and which does not interact with the components of the composition in a deleterious manner. Examples of nutritionally acceptable carriers include, for example, water, saline solutions, alcohols, silicones, waxes, petrolatum, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, oil of perfume, monoglycerides and diglycerides of fatty acids, esters of petroleum fatty acids, hydroxymethylcellulose, polyvinylpyrrolidone, etc. In some embodiments, the composition further includes any other ingredient or excipient known to be employed in the type of composition in question. Non-limiting examples of such ingredients include: proteins, amino acids, carbohydrates, oligosaccharides, lipids, nucleotides, nucleosides, other vitamins, minerals and other micronutrients. In certain embodiments, the composition contains a source of carbohydrates, for example in the form of prebiotics, or prebiotics when they are present in the composition. Any carbohydrate source commonly found in infant formula, such as lactose, sucrose, maltodextrin, starch, and mixtures thereof, may be used, although the preferred carbohydrate source is lactose. In certain embodiments, a composition according to the present description consists of a nutritional composition, for example a nutritional composition whose constitution is adapted to feed a human subject or else a non-human mammalian subject. Most preferably, in these embodiments, the composition is a nutritional composition for a human subject. Advantageously, a composition according to the invention, intended for oral administration, can be provided with a coating resistant to gastric juice, in order to ensure that the bacterial strain of the invention comprised in said composition can cross the damaged stomach. Release of the bacterial strain may thus occur for the first time in the upper intestinal tract. In certain embodiments, the nutritional composition is selected from whole food compositions, food supplements, nutraceutical compositions and the like. The composition of the present description can be used as a food ingredient and/or food ingredient for human subjects or non-human mammalian subjects. The food ingredient can be in the form of a solution or a solid, depending on the use and/or the mode of application and/or the mode of administration. As used herein, the term "food" refers to liquid (i.e. beverages), solid or semi-solid dietary compositions, in particular total food compositions (food replacement) , who does not require no additional supply of nutrients or dietary supplement compositions. Dietary supplement compositions do not completely replace the supply of nutrients by other means. As used herein, the term "food ingredient" encompasses a formulation that is or can be added to functional foods or foodstuffs as a dietary supplement. By "nutritional" or "nutraceutical" or "functional" food is meant a food material which contains ingredients having beneficial effects on health or capable of improving physiological functions. By "food supplement" is meant a food material intended to supplement a normal diet. A food supplement is a concentrated source of nutrients or other substances having a nutritional or physiological effect, when taken alone or in combination in small amounts. As used herein, "functional food" is used to designate food materials and corresponding products to which importance is attributed not only because of their nutritional and taste value but also because of the presence of ingredients having beneficial physiology. In some embodiments, the composition is a fermented dairy product or milk-based product, which is preferably administered or ingested orally one or more times per day. Fermented milk products include milk products, such as (but not limited to) desserts, yoghurts, yoghurt drinks, cottage cheese, kefir, fermented milk drinks, buttermilk , cheeses, salad dressings, low-fat spreads, cream cheese, soy drinks, ice cream, etc. Alternatively, in certain embodiments, the nutritional and/or nutritional supplement compositions may be non-dairy or unfermented dairy products. Unfermented dairy products can include ice cream, nutrition bars and seasonings, and others. Non-dairy products may include powdered drinks and nutrition bars, etc. Products can be made using known methods, such as adding an effective amount of F. prausnitzii bacteria, or a combination of bacteria including F. prausnitzii bacteria to a food base, such as skimmed milk or milk or a milk-based composition, and carry out a fermentation according to any known technique. In some embodiments, the composition is a beverage which may be a functional beverage or a therapeutic drink, thirst quencher or conventional drink. By way of example, the composition according to the present description can be used as an ingredient for soft drinks, a fruit juice or a drink comprising whey proteins, teas, cocoa drinks, milk drinks, yoghurts including drinkable yoghurts, cheeses, ice creams, popsicles and desserts, confectionery, cookies, cakes and cake mixes, snacks, healthy foods and beverages, frostings, acidified soy beverage/juice, aseptic/tapped chocolate beverage, bar mixes, powdered beverage mixes, calcium fortified soy milk and chocolate, calcium fortified coffee beverage. In some embodiments, the composition includes any other ingredient or excipient known to be employed in the type of composition in question. Non-limiting examples of such ingredients include: proteins, amino acids, carbohydrates, oligosaccharides, lipids, prebiotics or probiotics, nucleotides, nucleosides, other vitamins, minerals and other micronutrients. In certain other embodiments, F. prausnitzii bacteria, optionally in combination with probiotic bacteria of one or more other strains, are administered to the subject in the form of a pharmaceutical composition, which composition may consist of a product Live Biotherapeutic product (LBP) type reference: Front Med (Lausanne) Rouanet et al. 2020 Jun 19; 7: 237. Doi: 10.3389/fmed.2020.00237. For example, the bacteria of interest can be combined with pharmaceutically acceptable excipients, and optionally sustained release matrices, such as biodegradable polymers, to form therapeutic compositions. The terms "pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions which do not produce an adverse, allergic or other reaction when administered to a mammal, in particular a human, as the case may be. A pharmaceutically acceptable carrier or excipient means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid of any type. In the pharmaceutical compositions of the present description for administration particularly by the oral or rectal route, the active ingredient or the combination of active ingredients active ingredients, can be administered in unit dosage form, in mixture with conventional pharmaceutical carriers, to animals and humans. Suitable unit dosage forms include (i) oral dosage forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, including sublingual and orally, (ii) intranasally such as aerosols and (iii) rectally such as suppositories. The pharmaceutical composition must be stable under the conditions of manufacture and storage and must be preserved from the contaminating action of exogenous microorganisms, such as pathogenic bacteria and fungi. As used herein, the term "therapeutically effective amount", when used, is an equivalent term that refers to the amount of a therapy (e.g., prophylactic or therapeutic agent) that is sufficient to reduce the severity and/or duration of a disease, ameliorate one or more of its symptoms, prevent the progression of a disease or cause regression of a disease, or which is sufficient to result in the prevention of development, recurrence, onset, or progression of a disease or one or more of its symptoms, or to enhance or enhance the prophylactic and/or therapeutic effect(s) of another therapy (e.g., another therapeutic agent) useful for treating a disease. Typically, in a pharmaceutical composition according to the present description, the F. prausnitzii bacteria are present in an amount sufficient to induce a reduction in the viral load of a respiratory virus in the subject treated, when this subject is infected with said respiratory virus, relative to the expected viral load in a subject who has not received said F. prausnitzii bacteria. In a composition according to the description, whether it is a nutritional or food composition, where appropriate a food supplement, or whether it is a pharmaceutical composition, the bacteria or bacteria, in particular F. prausnitzii bacteria can be in various forms, for example in liquid form or in powder form. The bacteria or bacteria, in particular the F. prausnitzii bacteria, can be in freeze-dried form. The quantity of Faecalibacterium bacteria, in particular of F. prausnitzii or of F. duncaniae, which is supplied to the subject may be variable, depending on the physiological state of said subject, and in particular depending on whether the bacteria are administered for a prophylactic purpose or in a therapeutic purpose. The quantity of F. prausnitzii bacteria which must be provided to said subject can easily be adapted by those skilled in the art. In preferred embodiments, whether the composition is a nutritional composition or a pharmaceutical composition, the composition comprises an amount of bacteria of the genus Faecalibacterium which is suitable for daily intake, preferably daily oral intake, of at least 10 7 colony forming units (or "CFU" for "Colony Forming Units"). In these preferred embodiments, the daily intake, in particular the daily oral intake, of bacteria of the genus Faecalibacterium is at most 10 11 colony forming units (or “CFU” for “Colony Forming Units”). Thus, in certain preferred embodiments, the composition comprises an amount of bacteria of the Faecalibacterium genus ranging from 10 7 colony-forming units to 10 11 colony-forming units. In embodiments in which the composition further comprises other probiotic bacteria, the amount of such probiotic bacteria is determined by one skilled in the art based on his general knowledge. The amount of these other probiotic bacteria can vary from 10 3 to 10 13 other probiotic bacteria. In the embodiments in which the bacteria are inactivated, dead, or in the form of a bacterial extract or a bacterial lysate, the amount of daily intake is the equivalent of the amount of bacteria corresponding to the appropriate number of CFUs specified above. In certain embodiments, a composition according to the present description generally comprises carriers or vehicles. "Carriers" or "vehicles" refer to materials suitable for administration and include any material known in the state of the art, such as, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent or the like, which is non-toxic and which does not interact with the components of the composition in a deleterious manner. Examples of nutritionally acceptable carriers include, for example, water, saline solutions, alcohols, silicones, waxes, petrolatum, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, oil of perfume, monoglycerides and diglycerides of fatty acids, esters of petroleum fatty acids, hydroxymethylcellulose, polyvinylpyrrolidone, etc. In other embodiments of a composition according to the present description, as indicated elsewhere, said composition is in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. Such a pharmaceutical composition can be presented in the form of a package comprising a plurality of dosage units. The term "dosage unit" is used in its conventional sense in pharmacy (eg one pill, one capsule, one tablet, the contents of one ampoule, etc.). Uses This description relates to the prophylactic uses and the therapeutic uses of a composition as defined in the present application, against an infection of a subject by a respiratory virus, in particular against a infection of a human subject by a respiratory virus. The compositional characteristics, including of a prophylactic composition and a therapeutic composition, including in various embodiments, are described in detail in this description, which includes the amounts of active ingredient(s). ), especially the quantities of bacteria of the genus Faecalibacterium, in particular of bacteria of the species F. prausnitzii or of bacteria of the species F. duncaniae, included in these compositions. In certain embodiments, a prophylactic composition and a therapeutic composition according to the present description may have a qualitative and quantitative constitution in active ingredients and in excipient(s) which is identical, the only distinction being that the "prophylactic" composition is administered, as a preventive measure, to a subject not infected with a respiratory virus, whereas the same composition, this time qualified as “therapeutic”, is administered to a subject who is infected with a respiratory virus. In certain embodiments, a composition in accordance with the present description, optionally in the form of a dietary supplement composition, is formulated for daily administration, for example for daily administration in one or two doses, for example at meal times. In certain embodiments, a composition according to the present description, in particular a prophylactic composition according to the present description, is administered to the subject chronically, for a long period of time, for example for several months or even for several years. , for the purpose of mitigating the consequences of the possible occurrence of an infection by a respiratory virus, for example by a SARS-CoV-2 virus or else by an Influenza virus, in particular an Influenza virus of type A (IAV). In certain embodiments, a composition according to the present description, in particular a therapeutic composition according to the present description, is administered to a subject infected with a respiratory virus, (i) until the disappearance of the symptoms caused by the infection with said respiratory virus or (ii) until the presence of said respiratory virus in said subject becomes undetectable The invention is described below in more detail by means of the following examples which are presented by way of illustration uniquely. Examples Example 1: Effect of F. prausnitzii on the viral load of a respiratory virus A. Materials and Methods A.1. Treatment protocol 6-week-old female hamsters of the RjHan:AURA line obtained from Janvier Lab were used for the experiment. The hamsters were separated into two groups. A first group of hamsters was inoculated with the SARS-CoV-2 virus (UCN1 strain/GISAID identifier EPI_ISL_911513), by intranasal injection of a dose of 10 4 TCID 50 of the virus. A second group of hamsters was treated by oral administration of F. prausnitzii at the rate of a daily quantity of F. prausnitzii of 10 9 colony forming units (CFUs), during the 5 days preceding infection with SARS-CoV- 2, then for 4 days following inoculation with the SARS-CoV-2 virus. On D6, the hamsters were inoculated with the SARS-CoV-2 virus (UCN1 strain), by intranasal injection of a dose of 10 4 TCID 50 of the virus, as for the first group. The animals of the two groups were sacrificed on D4 following the inoculation of the SARS-CoV-2 virus. A.2. Viral load measurement protocols The evaluation of the viral load of the SARS-CoV-2 virus was carried out using lung samples taken from the animals on the day of their sacrifice. Detection of the SARS-CoV-2 viral genome was performed using a real-time PCR method. The detection of the SARS-COV-2 viral genome is based on the amplification of the E gene (position 26141-26253) by TaqMan RT-qPCR using a pair of nucleotide primers and a TaqMan probe described by Corman and para. (2020), The following method was carried out: - The viral RNA is extracted from 140 µL of clarified supernatant of organ tissue homogenate (diluted to 1/ 50th ) (ie lung) or from a volume of 140 µL of biological fluids (ie oropharyngeal swab diluted in a volume of 500 µL of DMEM medium containing 1% antibiotics). The extraction of the viral RNA is carried out using the commercial kit Qiagen Viral RNA mini kit (Qiagen, France) according to the manufacturer's instructions. The following nucleotide primers and the TaqMan probe were used: - E_Sarbeco_F1 ACAGGTACGTTAATAGTTAATAGCGT (SEQ ID NO. 1) - E_Sarbeco_R2 ATATTGCAGCAGTACGCACACA (SEQ ID NO. 2) - E_Sarbeco_P1 ACACTAGCCATCCTTACTGCGCTCG [5']'am [3']BHQ-1 ( SEQ ID NO.3). The primer pairs and the TaqMan probe have been described by Corman et al. Eurosurveillance; PMID:31992387. The primers allow amplification of the E gene (112-pB amplicon, position 26141-26253). TaqMan RT-qPCR was performed in a total volume of 25 µL TaqMan RT-qPCR assays were performed in a total volume of 25 µL containing 2.' μL of extracted RNA, 12.5 µL of 2x reaction mix, 1 µL of 225 mM MgCl (Invitrogen), 4.' µL of RNase-free water, 2 µL of each of the primers (10 µM), 0.25 µL of probe (10 µM) and 0.25 µL of enzyme (Quantitect Probe RT-mix). All assays were performed on the Rotor Gene Q MDx real-time thermal cycler (Qiagen, Courtaboeuf, France). Amplification was performed under the following thermocycling conditions: 50°C for 30 min for reverse transcription, followed by 95°C for 15 min and then 45 cycles of 94°C for 30 s, 55°C for 30 s and 72°C for 30 s. Negative and positive controls were included in each PCR. A standard curve was produced for each test in the following manner: production of a range of 5 dilutions to 1/ 10th from a calibrated SARS COV-2 RNA titrating 4.10^6' copies/µL of RNA. The Ct threshold of 0.05 was used as a reference for each RT-qPCR test. The efficiency, the slope and the correlation coefficient (R 2 ) were determined with the Rotor Gene software. All PCR reactions were performed in duplicate. The titration of the SARS-CoV-2 viral strain was carried out by infecting cells sensitive to the virus according to the following method: The titration of the infectious viral particles is carried out on 96-well microplates. A suspension of VeroE6 cells, sensitive to the SARS-CoV-2 virus, was prepared in DMEM medium containing 10% fetal bovine serum (FCS) and 1% antibiotics (penicillin/streptomycin/amphotericin B) so as to obtain a final concentration of 1.10 5 cells per ml. This cell suspension was seeded, in each well of the microplate, 24 hours before the inoculation of the samples. The microplates were incubated at 37°C in an oven containing 5% CO2. Twenty-four hours later, a first dilution of the sample to 1/10 is carried out in so-called "complete" medium, that is to say DMEM supplemented with fetal calf serum (10%) and a mixture penicillin/streptomycin (1%). Then from this diluted sample, serial dilutions of factor 4 are carried out in complete medium. The microplates containing the cell suspension are taken from the oven. Medium was removed from each well and immediately 50 µL of the 1/10 diluted suspension and serial quarter dilutions of each sample were added to each well in 6 replicates. After adding the inoculum, the plate was incubated at 37°C with 5% CO2 for one hour. Six uninfected wells were used as an independent negative control. One hour later, the microplate wells were filled with complete DMEM medium. After 3-4 days post-inoculation, plates were read under a white light microscope. Viral infection of susceptible cells by the SARS-CoV-2 virus causes cytopathic effects. The titer of the virus present in the samples, expressed in TCID50/mL, was determined using the Spe rman-Kärber formula: [Math 1] d ns which: - log10 (dilution50) = logarithm of the dilution where there is 50% of positive signal, i.e. 50% of lysis plaques - x0 = - (log10 of the lowest dilution with all the wells negative) - d = log10 of the dilution step - ri = number of negative wells - ni = number of C replicates. Results The results are presented in each of Figures 1 and 2. The results of Figures 1 and 2 show a statistically significant decrease of the viral load in the animals of the second group which was treated with F. prausnitzii, by comparison with the animals of the second group which did not receive F. prausnitzii, that the viral load be evaluated in number of copies of the genome of SARS-CoV-2 or in number of infectious virus particles. Example 2: Effect of F. prausnitzii on infection by the influenza virus (IAV H3N2) A. Materials and Methods A.1. Treatment protocol 8-week-old C57BL/6J male mice obtained from Janvier (Le Genest-St-Isle, France) were used for the experiment. The animals were separated into three groups. A first group of mice (n=5) received only the excipient (PBS-glycerol 16%) throughout the procedure and was not infected (MOCK control). A second group (n=8) received the excipient (PBS-glycerol 16%) and was inoculated after 5 days of treatment with the IAV virus (H 3 N 2 Strain Scotland/20/74), by intranasal injection of a dose of 50 PFU of virus per mouse. A third group of mice (n=10) was treated by oral (intragastric) administration of F. prausnitzii A2.165 at the rate of a daily quantity of F. prausnitzii of 5 x 10 9 colony forming units (CFUs) in buffer PBS-glycerol 16%, the 5 days preceding the infection. The mice were infected with the H 3 N 2 virus (Scotland/20/74 strain) by intranasal injection of a dose of 50 PFU of the virus. Treatment with F. prausnitzii was continued for 7 days after infection, until sacrifice. Weight was monitored daily after infection. A.2. Protocols for measuring the viral load The evaluation of the viral load of the IAV virus was carried out using lung samples taken from the animals on the day of their sacrifice. The measurement of the number of copies of the genome of the IAV virus was carried out according to the specific qRT-PCR method (Taqman method). The RNA was extracted from the lungs by grinding in RA1 buffer (Macherey Nagel) containing 1% β-mercaptoethanol. The RNA was retrotranscribed into cDNA by specific reverse transcription using primers recognizing the M1 region of the IAV virus (5ʹ-TCT AAC CGA GGT CGA AAC GTA-3ʹ - SEQ ID NO. 4). ) and SuperScript® II reverse transcriptase (Invitrogen). The PCR is carried out using TaqMan Universal PCR Master Mix (Applied Biosystems) and specific primers for the M1 region of IAV (sense: 5ʹ- AAG ACC AAT CCT GTC ACC TCT GA-3 – SEQ ID NO. 5ʹ anti-sense: 5ʹ-CAA AGC GTC TAC GCT GCA GTC C-3ʹ - SEQ ID NO. 6), and a specific TaqMan probe (marked FAM, TAMRA (5ʹ-TTT GTG TTC ACG CTC ACC GTG CC-3ʹ - SEQ ID NO. 7). The amplification was carried out on the Quantstudio 5 (Applied Biosystems). The number of copies was evaluated using a range of plasmids containing the gene of interest. A.3 Gene expression measurement protocol The expression of the different genes was carried out from lung samples taken from the animals on the day of their sacrifice.The expression of the genes was carried out according to the method by specific qRT-PCR (Sybergreen method). RNA was extracted from the lungs by grinding in RA1 buffer (Macherey Nagel) containing 1% β-mercaptoethanol. RNA was reverse-transcribed into cDNA using the High capacity RNA-t kit o-cDNA kit (Applied Biosystems). The qPCR was carried out using the Power SYBR green PCR master Mix (Applied Biosystems) and specific probes for each gene) and the amplification is carried out on the Quantstudio 5 (Applied Biosystems). The expression was related to that of a housekeeping gene (Gapdh) and compared (Expression relative to the expression obtained in uninfected control mice. C. Results C1. Impact of the F. prausnitzii A2-165 strain The impact of the reference strain F. prausnitzii A2-165 was first evaluated. The results are shown in each of Figures 3, 4, 5 and 6 and represent the average of 4 separate experiments. Figure 3 shows the weight loss induced by viral infection, either in kinetics after infection (Fig. 3A) or at D7 post-infection (Fig. 3B). The infected mice progressively lose weight to reach a significant weight loss compared to the uninfected animals (p<0.001). A significant decrease in weight loss (p<0.01) is observed in animals treated with F. prausnitzii A2-165, compared to animals which did not receive F. prausnitzii. Figure 4 shows the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 4A) or logarithmic (Fig. 4B) value. As expected, the viral load is significant in the infected mice (p<0.0001). The animals which have been treated with F. prausnitzii A2-165 show a very significant reduction (p<0.001) in the viral load compared to the animals which have not received F. prausnitzii. Figure 5 shows the clinical score evaluated by histological analyzes on lung sections stained with hematoxylin and eosin (H&E). This analysis shows a significant drop (p<0.05) in total scores (Fig. 5A), mainly due to a significant drop (p<0.05) in the percentage of lung lesions (Fig 5B), as well as a significant drop in the score d vascular inflammation (p=0.09) (FIG. 5C), in mice treated with the F. prausnitzii A2-165 strain. Figure 6 shows the expression of the genes encoding interferon gamma (Ifng) and of the genes induced by interferon gamma (Mx1 and Isg15) evaluated by qRT-PCR. This analysis shows that treatment with F. prausnitzii A2-165 limits the expression of these genes, induced by viral infection, which correlates with the decrease in viral load. Figure 7 shows the expression of pro-inflammatory genes encoding two chemokines involved in the recruitment of inflammatory cells (MCP1/CCL2 and CXCL2). This analysis shows that treatment with F. prausnitzii A2-165 limits significantly the expression of these genes, indicating that the treatment limits the inflammation at the pulmonary level. C2. Impact of the inactivation of the strain F. prausnitzii A2-165 Secondly, the impact of the reference strain F. prausnitzii A2-165 was compared with that of the same pasteurized strain (treatment of 30 minutes at 100 °C). The results are shown in each of Figures 7, 8 and 9 and represent the average of 2 separate experiments. Figure 8 shows the weight loss induced by viral infection, either in kinetics after infection (Fig. 8A) or on D7 post-infection (Fig. 8B). The infected mice progressively lose weight to reach a significant weight loss compared to the uninfected animals (p<0.0001). A similar decrease in weight loss is observed in animals treated with live or inactivated F. prausnitzii A2-165 strain, compared to animals that did not receive F. prausnitzii, however the effect is not significant. (p=NS). Figure 9 shows the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 9A) or logarithmic (Fig. 9B) values. As expected, the viral load is significant in the infected mice (p<0.0001). Animals which have been treated with live F. prausnitzii strain A2-165 show a significant decrease (p<0.01) in viral load compared to animals which have not received F. prausnitzii. A similar decrease is observed with the pasteurized strain A2-165. C3. Impact of the F. prausnitzii I-4574 strain The impact of another strain of F. prausnitzii, the I-4574 strain from the Micalis collection, was evaluated. The results are presented in each of Figures 10, 11, 12 and 13. Figure 10 shows the weight loss induced by viral infection, either in kinetics after infection (Fig.10A) or at D7 post-infection ( Fig.10B). The infected mice progressively lose weight to reach a significant weight loss compared to the uninfected animals (p<0.001). A similar decrease in weight loss is observed in animals treated with the two strains F. prausnitzii A2-165 and I-4574, administered live, compared to animals which did not receive F. prausnitzii. Figure 11 shows the viral load evaluated in number of copies of the genome of IAV by specific qRT-PCR (Taqman). The data is shown in linear (Fig. 11A) or logarithmic (Fig. 11B) values. As expected, the viral load is significant in infected mice (p < 0.01). The animals which have been treated with the F. prausnitzii I-4574 strain show a significant decrease (p<0.01) in the viral load compared to the animals which have not received F. prausnitzii. Figure 12 shows the expression of the genes encoding Interferon gamma (Ifng) and beta (Ifnb) and the gene induced by interferon gamma (Isg15) evaluated by qRT-PCR. This analysis shows that treatment with F. prausnitzii I-4574 significantly reduces the expression of interferons and, at the limit of significance, the expression of Isg15 (p=0.09) induced by the viral infection, which is correlated with decreased viral load. Figure 13 shows the expression of pro-inflammatory genes (Il6, Mcp1/Ccl2, Cxcl2) evaluated by qRT-PCR. This analysis shows that the treatment with F. prausnitzii I-4574 significantly reduces the expression of these genes (p<0.05-0.01), only the expression of Cxcl2 being at the limit of significance (p=0.09).
Claims
1. Bactéries du genre Faecalibacterium pour leur utilisation pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire, de préférence par un virus respiratoire humain. 1. Bacteria of the genus Faecalibacterium for their use in the prevention or treatment of an infection of a subject by a respiratory virus, preferably by a human respiratory virus.
2. Bactéries du genre Faecalibacterium pour leur utilisation selon la revendication 1, pour la prévention ou le traitement d’une infection d’un sujet par un virus respiratoire provoquant un syndrome aigu sévère de détresse respiratoire, de préférence par un virus humain. 2. Bacteria of the genus Faecalibacterium for their use according to claim 1, for the prevention or treatment of an infection of a subject by a respiratory virus causing severe acute respiratory distress syndrome, preferably by a human virus.
3. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 ou 2, lesdites bactéries étant choisies parmi les bactéries de l’espèce F. prausnitzii et les bactéries de l’espèce F. duncaniae. 3. Bacteria of the genus Faecalibacterium for their use according to one of claims 1 or 2, said bacteria being chosen from bacteria of the species F. prausnitzii and bacteria of the species F. duncaniae.
4. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 et 2, lesdites bactéries appartenant à la souche A2-165 ou à la souche déposée auprès de la CNCM sous le numéro d’accession CNCM 1-4574 le 7 décembre 2011. 4. Bacteria of the genus Faecalibacterium for their use according to one of claims 1 and 2, said bacteria belonging to the strain A2-165 or to the strain deposited with the CNCM under the accession number CNCM 1-4574 on December 7 2011.
5. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 à 4, ledit virus respiratoire étant choisi parmi (i) un virus respiratoire syncitial humain (HRSV), (ii) un virus humain parainfluenza (HPIV), (iii) un rhinovirus humain (HRV), (iv) un virus de la maladie Aléoutienne (ADV), (v) un coronavirus humain (HCoV), (vi) un metapneumovirus humain (HPMV), (vii) un bocavirus humain (HBoV), (viii) un virus parainfluenza humain (HIPV) (ix) un virus de l’influenza humain (IAV), (x) les rotavirus, (xi) les calicivirus, (xii) les torovirus, (xiii) les adenovirus, (xiv) les herpesvirus BHV et ADV et (xv) les pestivirus. 5. Bacteria of the genus Faecalibacterium for their use according to one of claims 1 to 4, said respiratory virus being chosen from (i) a human respiratory syncytial virus (HRSV), (ii) a human parainfluenza virus (HPIV), (iii ) human rhinovirus (HRV), (iv) Aleutian disease virus (ADV), (v) human coronavirus (HCoV), (vi) human metapneumovirus (HPMV), (vii) human bocavirus (HBoV) , (viii) human parainfluenza virus (HIPV) (ix) human influenza virus (IAV), (x) rotaviruses, (xi) caliciviruses, (xii) toroviruses, (xiii) adenoviruses, ( xiv) BHV and ADV herpesviruses and (xv) pestiviruses.
6. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 à 4, ledit virus étant un virus respiratoire SARS-CoV, de préférence un virus respiratoire SARS-CoV-2. 6. Bacteria of the Faecalibacterium genus for their use according to one of claims 1 to 4, said virus being a SARS-CoV respiratory virus, preferably a SARS-CoV-2 respiratory virus.
7. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 à 4, ledit virus étant un virus Influenza humain. 7. Bacteria of the genus Faecalibacterium for their use according to one of claims 1 to 4, said virus being a human Influenza virus.
8. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 à 4, pour réduire la charge virale du sujet en ledit virus respiratoire, de préférence la charge pulmonaire du sujet en ledit virus respiratoire.
8. Bacteria of the genus Faecalibacterium for their use according to one of claims 1 to 4, for reducing the subject's viral load of said respiratory virus, preferably the subject's lung load of said respiratory virus.
9. , Bactéries du genre Faecalibacterium pour leur utilisation selon la revendication 8, ledit virus respiratoire étant un virus SARS-CoV-2. 9. Bacteria of the genus Faecalibacterium for their use according to claim 8, said respiratory virus being a SARS-CoV-2 virus.
10. Bactéries de l’espèce F. prausnitzii pour leur utilisation selon la revendication 8, ledit virus respiratoire étant un virus Influenza humain. 10. Bacteria of the species F. prausnitzii for their use according to claim 8, said respiratory virus being a human Influenza virus.
11. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 à 8, lesdites bactéries étant comprises dans une composition, en association avec au moins un excipient physiologiquement acceptable. 11. Bacteria of the genus Faecalibacterium for their use according to one of claims 1 to 8, said bacteria being included in a composition, in combination with at least one physiologically acceptable excipient.
12. Bactéries du genre Faecalibacterium pour son utilisation selon l’une des revendications 1 à 11, lesdites bactéries étant comprises dans une composition sous une forme adaptée pour une administration par voie nasale, orale ou rectale. 12. Bacteria of the genus Faecalibacterium for use according to one of claims 1 to 11, said bacteria being included in a composition in a form suitable for nasal, oral or rectal administration.
13. Bactéries du genre Faecalibacterium pour leur utilisation selon l’une des revendications 1 à 12, ladite composition par voie orale étant choisie dans le groupe constitué d’un produit alimentaire, une boisson, un produit pharmaceutique, un nutraceutique, un additif alimentaire, un supplément alimentaire et un produit laitier. 13. Bacteria of the Faecalibacterium genus for their use according to one of claims 1 to 12, said oral composition being chosen from the group consisting of a food product, a drink, a pharmaceutical product, a nutraceutical, a food additive, a dietary supplement and a dairy product.
14. Bactéries du genre Faecalibacterium pour son utilisation selon l’une des revendications 1 à 13, lesdites bactéries étant comprises dans une composition sous une forme adaptée pour une administration de 107 à 1011 unités formant des colonies (ufc).
14. Bacteria of the genus Faecalibacterium for its use according to one of claims 1 to 13, said bacteria being included in a composition in a form suitable for administration of 10 7 to 10 11 colony-forming units (cfu).
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