WO2018220416A1 - Souche de lactobacillus paracasei capable d'améliorer la réponse immunitaire à une coinfection bactérienne et virale - Google Patents

Souche de lactobacillus paracasei capable d'améliorer la réponse immunitaire à une coinfection bactérienne et virale Download PDF

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WO2018220416A1
WO2018220416A1 PCT/IB2017/000812 IB2017000812W WO2018220416A1 WO 2018220416 A1 WO2018220416 A1 WO 2018220416A1 IB 2017000812 W IB2017000812 W IB 2017000812W WO 2018220416 A1 WO2018220416 A1 WO 2018220416A1
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infection
cncm
subject
lactobacillus paracasei
virus
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PCT/IB2017/000812
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Raphaëlle BOURDET-SICARD
Nouria BELKACEM
Muhamed-Kheir Taha
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Compagnie Gervais Danone
Bioaster
Institut Pasteur
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Priority to PCT/IB2017/000812 priority Critical patent/WO2018220416A1/fr
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    • 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
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to the field of probiotics and provides a Lactobacillus paracasei strain capable of improving the immune response to a viral-bacterial coinfection.
  • Influenza virus is a major source of severe viral respiratory infections in adults, causing annual epidemics that result in important morbidity and mortality.
  • Major pandemics in the 20 th century killed more than 100 million people.
  • a major part of the flu morbidity is also linked to secondary bacterial infections by bacteria that are known to share the respiratory tract as natural habitat and portal of entry such as Streptococcus pneumoniae, Neisseria meningitidis and other staphylococci (Hubert et al., 1992, Meningococcal disease and influenza-like syndrome: a new approach to an old question.
  • NA neuraminidases
  • cleavage of capsular sialic acid at the bacterial surface may unravel sub-capsular meningococcal adhesins and enhance meningococcal adhesion to epithelial cells.
  • the purpose of this invention is to fulfill this need by providing a Lactobacillus paracasei strain that can be used to enhance the immune response to a viral and bacterial coinfection.
  • the invention relates to a Lactobacillus paracasei strain deposited with the CNCM under the number 1-1518 for use in the treatment, the prevention or the alleviation of a coinfection consisting of a primary viral infection and a secondary bacterial Infection in a subject.
  • the Lactobacillus paracasei CNCM 1-1518 was deposited, according to the Budapest Treaty, at CNCM (Collection Nationale de Cultures de Microorganismes, 25 rue du Dondel Roux, Paris, France) on December 30, 1994 with the reference CNCM 1-1518.
  • the coinfection also called superinfection
  • the coinfection refers to the pathological state wherein a subject successively develops a primary infection and a secondary infection, the secondary infection occurring before the recovery from the primary infection.
  • a subject is considered as suffering from a coinfection when he is contaminated by the pathogen responsible of the secondary infection, while being still infected by the pathogen responsible of the primary infection and up to the recovery of both infections.
  • a subject is necessarily infected by two distinct pathogens at the beginning of the coinfection, but he can remain infected by only one of these two pathogens during later phases of the coinfection.
  • the subject is necessarily infected by a virus and a bacterium at the beginning of the coinfection, but he can remain infected by said virus only, or by said bacterium only, until the end of the coinfection.
  • L. paracasei strain CNCM 1-1518 can be used for the treatment, the prevention or the alleviation of the viral-bacterial coinfection (the subject is infected by the virus and the bacterium), the residual secondary bacterial infection (the primary viral infection has been cured and the subject remains infected by the bacterium only) and/or the residual primary viral infection (the secondary bacterial infection has been cured and the patient remains infected by the virus only).
  • the subject is infected (or suffering from an infection) if the clinical symptoms usually associated to the infection are detected and/or if the presence of the pathogen responsible of the infection is detected in the subject's body.
  • a subject has recovered from an infection (or is no longer infected; or is no longer suffering from an infection) if the clinical symptoms associated to the infection are no longer detected and/or if the presence of the pathogen responsible of the infection is no longer detected in the subject's body.
  • the present invention is based on the unexpected observation made by the Inventors that L. paracasei strain CNCM 1-1518 is capable of improving the protection to a bacterial infection occurring during a viral infection, even if this bacterial infection occurred 7 days after the viral infection, timing when the immune system is dampened compared to control group.
  • the coinfection occurs between 5 and 15 days, in particular between 7 and 10 days after the contamination by the pathogen responsible of the primary infection.
  • the subject can be contaminated by the pathogen responsible of the secondary infection between 5 and 15 days, in particular between 7 and 10 days after being contaminated by the pathogen responsible of the primary infection.
  • the subject is contaminated by the pathogen responsible of a secondary infection during the week, or the two weeks, following the contamination by the pathogen responsible of the primary infection.
  • the subject is contaminated by the pathogen responsible of the secondary infection 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days after the contamination by the pathogen responsible of the primary infection.
  • the flu infection comprises an early stage with symptoms of fever, aches, diffuse pain, followed by a late stage of damage of the epithelium respiratory tract (cough, rhino pharyngitis and even bronchitis or bronchopneumonia).
  • the patient can develop a bacterial bronchopneumonia and/or an invasive bacterial infection (entry of the bacteria in the blood and dissemination).
  • the coinfection occurs during the early stage of a flu primary infection.
  • the coinfection occurs during the late stage of a flu primary infection.
  • the subject is an animal, preferably a mammal, more preferably a human.
  • the invention relates to the Lactobacillus poracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by a virus selected from the group consisting of Influenza A virus (IAV), influenza B virus (IBV), parainfluenza virus, adenovirus, rhinovirus, coronavirus, respiratory syncytial virus (RSV), coxsackie virus, in particular IAV.
  • a virus selected from the group consisting of Influenza A virus (IAV), influenza B virus (IBV), parainfluenza virus, adenovirus, rhinovirus, coronavirus, respiratory syncytial virus (RSV), coxsackie virus, in particular IAV.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primal viral infection is responsible of the flu.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for Its use as defined above, wherein the secondary bacterial infection is selected from the group consisting of: a meningococcal infection, a pneumococcal infection, a staphylococcal infection, an haemophilus infection, a pseudomonas infection, a mycoplasma infection, a chlamydia infection, a moraxella infection, in particular a meningococcal infection.
  • the secondary bacterial infection is selected from the group consisting of: a meningococcal infection, a pneumococcal infection, a staphylococcal infection, an haemophilus infection, a pseudomonas infection, a mycoplasma infection, a chlamydia infection, a moraxella infection, in particular a meningococcal infection.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the secondary bacterial infection is caused by a bacterium selected from the group consisting of: Neisseria meningitidis, Haemophilus influenza, Streptococcus pneumoniae, Staphyloccocus aureus, Pseudomonas aeruginosa, Mycoplasma pneumoniae, Chlamydia pneumonia, Moraxella catarrhalis, in particular Neisseria meningitidis.
  • the Invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the secondary bacterial infection is responsible of the meningitis.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the virus and the bacterium colonize the same area of the body of the subject.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the virus and the bacterium colonize the respiratory tract.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the virus and the bacterium colonize the upper respiratory tract.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the virus and the bacterium colonize the lower respiratory tract.
  • the "upper respiratory tract” comprises the nasal cavity and associated sinuses, the nasopharynx, the oropharynx, the larynx and the trachea, while the 'lower respiratory tract” comprises the bronchi, the bronchioles and the terminal bronchioles and the lungs.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the virus and the bacterium colonize the lungs.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by an influenza virus, preferably IAV, and the secondary bacterial infection is caused by Neisseria meningitidis.
  • the primary viral infection is caused by an influenza virus, preferably IAV
  • the secondary bacterial infection is caused by Neisseria meningitidis.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by an influenza virus, preferably IAV, and the secondary bacterial infection is caused by Streptococcus pneumoniae.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by an influenza virus, preferably IAV, and the secondary bacterial infection is caused by Staphylococcus aureus.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by an influenza virus, preferably IAV, and the secondary bacterial infection is caused by Pseudomonas aeruginosa.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by the respiratory syncytial virus and the secondary bacterial infection is caused by Streptococcus pneumoniae.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary viral infection is caused by the respiratory syncytial virus and the secondary bacterial infection is caused by Haemophilus influenzae.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primary virai infection is caused by the respiratory syncytial virus and the secondary bacterial infection is caused by Staphyloccus aureus.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the primal viral infection is responsible of the flu and the secondary bacterial infection is responsible of the meningitis.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the level of at least one inflammatory cytokine in the respiratory tract and/or in the lungs of the subject that has consumed L. paracasei CNCM 1-1518 is increased compared to the level of said at least one inflammatory cytokine in the same body area of a control subject that has not consumed L. paracasei CNCM 1-1518, in particular 48 hours after the contamination by the bacterium responsible of the secondary infection.
  • the level of at least one cytokine is increased by at least 5%, 10%, 1596, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% in the subject that has consumed L. paracasei CNCM 1-1518 compared to the control subject that has not consumed L paracasei CNCM 1-1518.
  • the pro-inflammatory cytokines include, but are not limited to, IL6, MCP1, KC and IL12p70.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the level of IL6, MCP1, KC and IL12p70 in the respiratory tract and/or in the iungs of the subject that has consumed L. paracasei CNCM 1-1518 is increased compared to the level of IL6, MCP1, KC and IL12p70 in the same body area of a control subject that has not consumed L. paracasei CNCM 1-1518, in particular 48 hours after the contamination by the bacterium responsible of the secondary infection.
  • the level of cytokines can be determined by various methods well known to one skilled in the art. In particular, it can be determined using an EUSA kit and compared to total protein content using a BSA protein assay as described in the examples.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the recruitment of immune cells in the respiratory tract and/or in the lungs of the subject that has consumed L paracasei CNCM 1-1518 is increased compared to the recruitment of immune cells In the same body area of a control subject that has not consumed L paracasei CNCM 1-1518, in particular 48 hours after the contamination by the bacterium responsible of the secondary infection.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the recruitment of at least one population of immune cells in the respiratory tract and/or in the lungs of the subject that has consumed L. paracasei CNCM 1-1518 Is increased compared to the recruitment of said population of immune cells in the same body area of a control subject that has not consumed L paracasei CNCM 1-1518, in particular 48 hours after the contamination by the bacterium responsible of the secondary infection, said population of immune cells being selected from the group comprising dendritic cells (DCs), macrophages, monocytes, neutrophils, eosinophils and B cells, preferably from the group comprising dendritic cells, monocytes and neutrophils.
  • DCs dendritic cells
  • B cells preferably from the group comprising dendritic cells, monocytes and neutrophils.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the recruitment of dendritic cells (DCs), macrophages, monocytes, neutrophils, eosinophils and B cells in the respiratory tract and/or In the lungs of the subject that has consumed L. paracasei CNCM 1-1518 is Increased compared to the recruitment of dendritic cells (DCs), macrophages, monocytes, neutrophils, eosinophils and B cells in the same body area of a control subject that has not consumed L paracasei CNCM 1-1518, in particular 48 hours after the contamination by the bacterium responsible of the secondary infection.
  • DCs dendritic cells
  • macrophages monocytes
  • neutrophils neutrophils
  • eosinophils and B cells in the same body area of a control subject that has not consumed L paracasei CNCM 1-1518, in particular 48 hours after the contamination by the bacterium responsible of the secondary infection.
  • the recruitment of at least one population of immune cells Is increased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% in the subject that has consumed L paracasei CNCM 1-1518 compared to the control subject that has not consumed L paracasei CNCM 1-1518.
  • the recruitment of immune cells can be determined by various methods well known to one skilled in the art. In particular, it can be determined by flow cytometry as described in the examples.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the bacterial load of the bacterium responsible of the secondary infection in the respiratory tract and/or in the lungs of the subject that has consumed L paracasei CNCM I- 1518 is reduced compared to the bacterial load of said bacterium in the same body area of a control subject that has not consumed L paracasei CNCM 1-1518, in particular 24 hours, more particularly 48 hours after the contamination by said bacterium.
  • the bacterial load corresponds to the measurable quantity of a bacterium in the body of a subject.
  • the bacterial load of the bacterium responsible of the secondary infection is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% in the subject that has consumed L. paracasei CNCM 1-1518 compared to the control subject that has not consumed L paracasei CNCM 1-1518.
  • the bacterial load of the bacterium can be determined by various methods well known to one skilled in the art.
  • the bacterial load of the bacterium can be determined by bioluminescence or by using culture from a biological sample and counting on petri dishes.
  • the invention relates to the Lactobacillus paracosei strain CNCM 1-1518 for its use as defined above, wherein said subject is selected from the group comprising a vulnerable subject, an immune depressed subject, an hospitalized patient, a child and an elderly individual aged 65 or over.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein said subject does not suffer from a chronic and/or latent infection, such as an infection by HSV (Herpes Simplex Virus), CMV (Cytomegalovirus) and HIV (Human Immunodeficiency virus).
  • HSV Herpes Simplex Virus
  • CMV Cytomegalovirus
  • HIV Human Immunodeficiency virus
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein said subject suffers from a chronic and/or latent infection, such as an infection by HSV, CMV and HIV.
  • a chronic infection refers to a long term infection, in general for more than 3 months.
  • a latent infection refers to an asymptomatic infection capable of manifesting symptoms under particular circumstances or If activated.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein said strain is used in addition of a vaccination. In an embodiment, the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein said strain is used in addition of a treatment by antibiotics.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein the subject consumes at least one daily dose of L paracasei CNCM 1-1518 during the period prior to, and/or during, the coinfection.
  • the invention relates to the Lactobacillus paracasei strain CNCM I- 1518 for its use as defined above, wherein the subject has started to consume at least one dally dose of L. paracasei CNCM 1-1518 before the secondary infection, more preferably before the primary infection.
  • At least one daily dose of L. paracasei strain CNCM 1-1518 is consumed for at least one week, preferably for at least two weeks, more preferably for at least three weeks, even more preferably for four weeks, before the contamination by the bacterium responsible for the secondary infection, preferably before the contamination by the virus responsible for the primary infection.
  • L paracasei strain CNCM 1-1518 may subsequently be continued for as long as desired so as to maintain the effect of the L paracasei strain against the coinfection.
  • the amount of L paracasei strain CNCM 1-1518 consumed dairy will preferably be at least 10 10 , advantageously at least 2x1 ⁇ 10 CFU. This amount can be administered in one or more daily intakes.
  • a daily dose contains at least 10 s , preferably at least 10 s , and generally between lxlO 8 and 1.5x10 s L paracasei cells per ml.
  • the invention relates to the L. paracasei strain CNCM 1-1518 for its use as defined above, wherein said L. paracasei strain is contained in an oraHy administrate composition.
  • the invention relates to the Lactobacillus paracasei strain CNCM 1-1518 for its use as defined above, wherein said composition is a food product or a food supplement, in particular a fermented dairy product, more particularly a yoghurt.
  • the L paracasei strain CNCM 1-1518 may be used alone, or in combination with other tactic acid bacteria of the L. paracasei species or of other species.
  • it may be used in combination with yogurt ferments, namely Lactobacillus bulgaricus and Streptococcus thermophilus.
  • the composition advantageously comprises at least 10 7 , preferably between 2x10 s and lxlO 9 S. thermophilus cells per ml, and at least 5x10 s , preferably between 4xl0 6 and 2xl0 7 L. bulgaricus cells per ml.
  • the present invention also relates to a method of treatment, prevention or alleviation of a coinfection consisting of a primary viral infection and a secondary bacterial infection in a subject comprising administering to said subject an effective amount of Lactobacillus paracasei strain CNCM 1-1518.
  • the present invention also relates to the use of Lactobacillus paracasel strain CNCM 1-1518 for the manufacture of a medicament for the treatment, the prevention or the alleviation of a coinfection consisting of a primary viral infection and a secondary bacterial infection in a subject.
  • FIG. 1 Invasive meningococcal Infections and influenza-like Illnesses recorded in France by the Reference Center for Meningococci and the Sentinelles Network from January 2000 to May 2007. Reporting of invasive meningococcal infections is mandatory. All invasive meningococcal isolates in France are sent to the National Reference Center for Meningococci for full characterization and typing. The general practitioners of the Sentinelles Network report on influenza-like illnesses on a weekly basis by sending patient deidentified data via the Internet to a G IS database. The monthly incidence of MD (right axis) and the weekly incidence of influenza-like illnesses (left axis) during the period of January 2000 to May 2007 are represented on the same graph, (adapted from Rameix- Welti et ai, 2009).
  • FIG. 1 Effects of L paracasei consumption on health status of influenza/Nm-infected mice.
  • A Schematic representation of the experimental design.
  • B Body weight loss,
  • C score appearance and
  • FIG. 3 Dissemination of N. meningitidis in BALB/c-flu infected mice. Sequential IAV (250 PFU per mouse) and meningococcal infection (10 7 CFU per mouse) were performed by intranasal route. Bacterial infection was analyzed for bioluminescence at the indicated times. Images depict photographs overlaid with colour representations of luminescence intensity, measured in total photons/sec and indicated on the scales, where red is most intense and blue is least intense. (A) Ventral views of 9 mice (PBS-fed) and 10 mice (L paracasei-ied mice). A non-infected mouse was added as a control. (B). The luminescence was quantified and expressed as means ⁇ SEM from each category at the indicated times by defining specific representative region of interest encompassing the entire animal.
  • aM Alveolar Macrophage
  • i ' M Interstitial Macrophage
  • DC Dendritic cells
  • iM Inflammatory Monocyte
  • pM Patrolling monocytes
  • Eo Eosinophils
  • N Neutrophils
  • B B cells
  • T T cells. Results are expressed as mean ⁇ SEM for each group. (*p ⁇ 0.05, **P ⁇ 0.01).
  • Neisseria meningitidis (Nm) bioluminescent derivative of strain 24198 (serogroup C) was cultured on GCB agar medium (Difco).
  • Influenza A virus (IAV) (A/Scotland/20/74 (H3N2)) adapted to mice was made from lung homogenates in 3096 glycerol and stored at -80"C. The virus was prepared, stored in aliquots at -80*C and thawed prior to infection as previously described (Alonso et a/., 2003).
  • mice Six-week old female BALB/c mice were purchased (Janvier, Genest-Saint-lsle, France) and kept one week prior to the experiment in biosafety containment facility. All mice were housed under specific pathogen free condition at the Institut Pasteur, provided with food and water ad libitum. Experimental animals were performed in accordance with guidelines of the Animal Care Use Committee at the Institut Pasteur and were approved by the French Research Ministry.
  • mice were daily orally gavaged (200 ⁇ ) with L paracasei (2x10* colony forming unit, CFU) or PBS (control) for 7 days (Figure 2A). At day 0 (DO), mice were lAV-infected. At day 7 (D7), 7 days after IAV infection, mice were surinfected with N. meningitidis and followed up to 48 hours after secondary infection. Oral gavage with probiotic was performed during the whole period of viral Infection and secondary infection.
  • L paracasei 2x10* colony forming unit, CFU
  • PBS control
  • Viral infection was performed intranasally on mice that were anesthetized with sodium pentobarbital (Sanofi, Sante Animale, Libourne France) before an intranasal infection with 50 ⁇ of virus H3N2 (260 plaque forming unit, PFU).
  • the secondary meningococcal infection was performed 7 days post- influenza virus infection.
  • the secondary bacterial infection was followed by bioluminescence using bioluminescent N. meningitidis LNP24198lux, a serogroup C isolate belonging to the hyper invasive clonal complex ST-11.
  • Intranasal infection was performed similarly to the flu infection by administration of 50 ⁇ of or bacterial suspension at 2x10 s CFU/ml (10 7 CFU per mouse) as previously described (Alonso et al., 2003).
  • mice Health status, appearance score and survival of mice was followed after IAV infection at day 0 and followed during 16 days. Weight and fur appearance of each mouse were daily measured. Results were expressed as body weight loss compared to values at DO. Fur appearance was also scored after infection at DO as follows: 3-Coat is smooth; 2-Patches of hair piloerected; 3-Majority of back is piloerected, and O-Piloerection may or may not be present, mouse appears "puffy" ( Shrum et al., A robust scoring system to evaluate sepsis severity in an animal model, BMC research notes 7:233, 2014). Survival of mice was scored and represented as percent survival.
  • mice were sacrificed at the end of experiment. After perfusion, lungs were extracted, homogenized and divided into two lots and used to perform the cytokine assay and flow cytometry analysis.
  • mice infected intranasal ⁇ with bioluminescent N. meningitidis were anesthetized using a constant flow of 2.5% isoflurane mixed with oxygen, using an XGI-8 anesthesia induction chamber (Xenogen Corp.).
  • Bacterial infection images were acquired using an MS 100 system (Xenogen Corp., Alameda, CA) according to instructions from the manufacturer. Analysis and acquisition were performed using Living Image 3.1 software (Xenogen Corp.). Images were acquired using l min of integration time with a binning of 16. All other parameters were held constant. Quantifying was performed using the photons per second emitted by each mouse by defining regions of interest (lung). An uninfected mouse in the same conditions of acquisition was used for subtracting the background.
  • cytokine levels in the lungs were expressed as the amount of cytokine per unit weight of total protein of lung.
  • the quantification of total protein was determined using BSA protein Assay Kit (Thermos scientific, Meridian Road, USA) according to the manufacturer's instructions.
  • EXAMPLE 1 Effects of L oaracasel on secondary bacterial-Infected mke hearth status
  • mice also seemed ill according to a clinical score based on the fur appearance, this score was significantly better in L paracasei -fed mice than in PBS-fed mice at days 3, 4, S, 6 and 7 post-infection (Figure 2C).
  • Figures 2B and 2C we observed less weight lost in L paracasei group, with a better clinical score.
  • L paracasei group of mice showed better survival (90%) at day 9 compared to the 75% survival rate in PBS-fed-mice ( Figure 2D).
  • N. meningitidis infection was followed by dynamic bioluminescence imaging.
  • the quantification of bacterial load was performed in LAV infected mice in both the two groups: treated with L paracasei or with PBS, using the total photons per second emitted by each mouse after 0.5h, 3h, 6h, 24h and 48h of infection ( Figure 3).
  • cytokine levels in the lungs were determined and expressed as the amount of cytokine per mg of total protein of tested lungs.
  • Example 4 Effect of consumption of L paracasei on the recruitment of immune cells In lungs
  • the total cells counts in the lung cell suspensions were quantified using trypan blue, at day 0 (just before primary infection by IAV, Figure 6A), at day 7 (just before secondary infection by N. meningitidis. Figure 6B) or at day 9 (48h after the secondary infection with N. meningitidis, Figure 7).
  • This quantification showed higher significant counts of total cells at D9 in the lungs of group of mice orally gavaged with L. paracasei than in control group ( Figure 7A).

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Abstract

L'invention concerne le domaine des probiotiques et fournit une souche de Lactobacillus paracasei pouvant améliorer la réponse immunitaire à une co-infection bactérienne et virale.
PCT/IB2017/000812 2017-05-31 2017-05-31 Souche de lactobacillus paracasei capable d'améliorer la réponse immunitaire à une coinfection bactérienne et virale WO2018220416A1 (fr)

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WO2022164012A1 (fr) * 2021-02-01 2022-08-04 주식회사 엠디헬스케어 Composition comprenant des vésicules dérivées de lactobacillus paracasei pour prévenir, traiter ou soulager des maladies infectieuses virales ou des maladies respiratoires
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WO2023120547A1 (fr) * 2021-12-22 2023-06-29 株式会社明治 Composition pour prévenir des maladies sexuellement transmissibles secondaires ou réduire le risque de développer celles-ci
CN117398417A (zh) * 2023-10-24 2024-01-16 广东南芯医疗科技有限公司 副干酪乳杆菌e6在制备抗抑郁药物中的应用

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WO2022164012A1 (fr) * 2021-02-01 2022-08-04 주식회사 엠디헬스케어 Composition comprenant des vésicules dérivées de lactobacillus paracasei pour prévenir, traiter ou soulager des maladies infectieuses virales ou des maladies respiratoires
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CN113249244A (zh) * 2021-03-25 2021-08-13 上海理工大学 一种拮抗咽炎致病菌乙型溶血性链球菌的副干酪乳杆菌
WO2023120547A1 (fr) * 2021-12-22 2023-06-29 株式会社明治 Composition pour prévenir des maladies sexuellement transmissibles secondaires ou réduire le risque de développer celles-ci
CN116064295A (zh) * 2022-09-09 2023-05-05 青岛蔚蓝生物股份有限公司 一株具有抑制流感嗜血杆菌功能的副干酪乳酪杆菌及其应用
CN117398417A (zh) * 2023-10-24 2024-01-16 广东南芯医疗科技有限公司 副干酪乳杆菌e6在制备抗抑郁药物中的应用

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