WO2021027181A1 - 含铁物质在制备抑制登革病毒传播的产品中的应用 - Google Patents

含铁物质在制备抑制登革病毒传播的产品中的应用 Download PDF

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WO2021027181A1
WO2021027181A1 PCT/CN2019/120582 CN2019120582W WO2021027181A1 WO 2021027181 A1 WO2021027181 A1 WO 2021027181A1 CN 2019120582 W CN2019120582 W CN 2019120582W WO 2021027181 A1 WO2021027181 A1 WO 2021027181A1
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iron
dengue virus
aedes aegypti
virus
dengue
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程功
朱毅斌
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Tsinghua University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the application of iron-containing substances in the preparation of products that inhibit the spread of dengue virus.
  • Aedes aegypti is a kind of insects that acquire and spread viruses by sucking blood, and is the culprit of dengue fever.
  • "Dengue fever” is an acute mosquito-mediated infectious disease that is prevalent in tropical and subtropical regions. It has the characteristics of fast transmission and high incidence. The virus transmitted by mosquitoes will show clinical symptoms such as encephalitis, meningitis, and hemorrhagic fever. It has caused hundreds of millions of infections and hundreds of thousands of deaths, causing serious harm to world public health.
  • Iron supplementation is a medical method that is generally applicable to iron-deficient and low-iron populations, but so far there is no relevant report that iron supplementation can effectively reduce the susceptibility of Aedes aegypti to dengue virus.
  • the technical problem to be solved by the present invention is how to inhibit the spread of dengue virus.
  • the present invention first discloses the application of iron-containing substances in the preparation of products that inhibit the spread of dengue virus.
  • the present invention further discloses the application of iron-containing substances in the preparation of products for inhibiting the susceptibility of mosquitoes to dengue virus.
  • the present invention also provides a method for inhibiting the spread of dengue virus.
  • the method for inhibiting the spread of dengue virus of the present invention includes administering the above-mentioned iron-containing substance to a host infected with dengue virus, thereby inhibiting the spread of dengue virus.
  • the present invention further provides a method for inhibiting the susceptibility of mosquitoes to dengue virus, which comprises administering the above-mentioned iron-containing substance to a host infected with dengue virus, thereby inhibiting the susceptibility of mosquitoes to dengue virus.
  • the active ingredient of the iron-containing substance is an iron-containing compound; the iron-containing substance may be a pure substance or a mixture; specifically, the iron-containing substance may be an iron supplement.
  • the active ingredient of the iron-containing substance may be ferric ammonium citrate.
  • the product can be food, medicine or health care products, and so on.
  • the product may also contain suitable carriers or excipients.
  • suitable carriers or excipients include, but are not limited to, water-soluble carrier materials (such as polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (such as ethyl cellulose, cholesterol stearate, etc.), enteric carriers Materials (such as cellulose acetate phthalate and carboxymethyl cellulose, etc.). Among them, water-soluble carrier materials are preferred.
  • Using these materials can be made into a variety of dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, Buccal tablets, suppositories, freeze-dried powder injections, etc. It can be ordinary formulations, sustained-release formulations, controlled-release formulations, and various particle delivery systems. In order to make a unit dosage form into a tablet, various carriers known in the art can be widely used.
  • carriers are, for example, diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, acacia syrup, gelatin syrup, sodium carboxymethyl cellulose , Shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dried starch, alginate, agar powder, algal starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, Sorbitol fatty acid ester, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose, etc.; disintegration
  • the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multilayer tablets.
  • coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multilayer tablets.
  • various carriers known in the art can be widely used.
  • Examples of carriers are, for example, diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , Ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, such as agar powder, dried starch, alginate, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose, etc.
  • various carriers known in the art can be widely used.
  • Examples of carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.
  • all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1, 3-Propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, etc.
  • an appropriate amount of sodium chloride, glucose or glycerol can be added to the injection preparation, and in addition, conventional solubilizers, buffers, pH adjusters, etc. can also be added.
  • coloring agents, preservatives, flavors, flavors, sweeteners, or other materials can also be added to the pharmaceutical preparations.
  • the above dosage forms can be administered by injection, including subcutaneous injection, intravenous injection, intramuscular injection and intracavity injection, etc.; cavity administration, such as rectum and vagina; respiratory administration, such as nasal cavity; mucosal administration.
  • the mosquito is Aedes aegypti or other mosquitoes capable of transmitting viruses.
  • the dengue virus is dengue virus type-2 (DENV-2).
  • the host infected by the dengue virus may be an iron-deficient or low-iron animal, and may be a mammal, such as humans and mice.
  • Figure 1 shows the effect of ferric ammonium citrate on the infection rate of dengue virus in Aedes aegypti; each open dot represents an Aedes aegypti.
  • Figure 2 shows the effect of iron-deficient mice on the infection rate of dengue virus in Aedes aegypti; each open dot represents an Aedes aegypti.
  • Figure 3 shows the determination of serum iron in iron-deficient mice and normal mice. Each open circle represents a mouse.
  • Figure 4 shows the effect of iron supplementation in iron-deficient mice on the dengue virus infection rate in the intestinal tissue of Aedes aegypti; each open dot represents an Aedes aegypti mosquito.
  • Figure 5 shows the effect of iron supplementation in iron-deficient mice on the dengue virus infection rate in the salivary glands of Aedes aegypti; each open dot represents one Aedes aegypti.
  • Aedes aegypti is in the document "ColpittsTM et al.Alterations in the Aedes aegypti Transcriptome during Infection with West Nile, Dengue and Yellow Fever Viruses.2011, PloSPathog 1002189.”: It has been made public, and the public can obtain it from Tsinghua University School of Medicine.
  • the New Guinea C strain of dengue virus type-2 (DENV-2) is in the document "Liu et al. Flavivirus NS1 protein in infected host sera enhancement viral acquisition by mosquitoes. 2016, Nat Microbiol” 1(9):16087.” It was published in “, and the public can obtain it from the School of Medicine of Tsinghua University.
  • ferric ammonium citrate was purchased from Sigma, and the product catalog number is F5879.
  • the iron-deficient feed in the following examples was purchased from Nantong Trofi Feed Technology Co., Ltd., article number: TP0306.
  • Example 1 In vitro membrane feeding system feeding ferric ammonium citrate inhibits the susceptibility of dengue virus in Aedes aegypti
  • Feeding ferric ammonium citrate with an extracorporeal membrane feeding system can reduce the infection rate of Aedes aegypti to dengue virus.
  • the specific test is as follows:
  • Aedes aegypti into 4 groups, namely control group, 25 ⁇ M FAC group, 50 ⁇ M FAC group and 150 ⁇ M FAC group, and perform the following treatments respectively:
  • Control group Each Aedes aegypti mosquito was fed a mixture of human anticoagulated whole blood sample and Dengue 2 virus (DENV-2) supernatant (1:1 volume ratio) through an extracorporeal membrane feeding system;
  • DEV-2 Dengue 2 virus
  • FAC group each Aedes aegypti was fed human anticoagulated whole blood samples containing ferric ammonium citrate (FAC) and dengue 2 virus (DENV-2) supernatant (1:1 volume) through an extracorporeal membrane feeding system Compared with the mixed solution of), the concentration of the ferric ammonium citrate in the mixed solution is 25 ⁇ M.
  • FAC group each Aedes aegypti was fed human anticoagulated whole blood samples containing ferric ammonium citrate (FAC) and dengue 2 virus (DENV-2) supernatant (1:1 volume) through an extracorporeal membrane feeding system Compared with the mixed solution of), the concentration of the ferric ammonium citrate in the mixed solution is 50 ⁇ M.
  • FAC group each Aedes aegypti was fed human anticoagulated whole blood samples containing ferric ammonium citrate (FAC) and dengue 2 virus (DENV-2) supernatant (1:1 volume) through an extracorporeal membrane feeding system Compared with the mixed solution of), the concentration of the ferric ammonium citrate in the mixed solution is 50 ⁇ M.
  • FAC group each Aedes aegypti was fed human anticoagulated whole blood samples containing ferric ammonium citrate (FAC) and dengue 2 virus (DENV-2) supernatant (1:1 volume) through an extracorporeal
  • FAC group Each Aedes aegypti was fed human anticoagulated whole blood samples containing ferric ammonium citrate (FAC) and Dengue 2 virus (DENV-2) supernatant (1:1 volume) through an extracorporeal membrane feeding system Compared with the mixed solution of), the concentration of the ferric ammonium citrate in the mixed solution is 150 ⁇ M.
  • the primers used to detect Dengue 2 virus are as follows:
  • Upstream primer 5'-CATTCCAAGTGAGAATCTCTTTGTCA-3' (sequence 1);
  • Downstream primer 5'-CAGATCTCTGATGAATAACCAACG-3' (sequence 2).
  • the primers of Actin gene used are as follows:
  • Upstream primer 5'-GAACACCCAGTCCTGCTGACA-3' (sequence 3);
  • Downstream primer 5'-TGCGTCATCTTCTCACGGTTAG-3' (sequence 4).
  • Control group indicated by “control group” in the figure
  • 25 ⁇ M FAC group indicated by “25 ⁇ M FAC” in the figure
  • 50 ⁇ M FAC group indicated by “50 ⁇ M FAC” in the figure
  • 150 ⁇ M FAC group indicated by "150 ⁇ M in the figure
  • the infection status of Dengue 2 virus in Aedes aegypti mosquitoes represented by FAC is shown in Figure 1.
  • Example 2 The iron-deficiency mouse model significantly improves the susceptibility of dengue virus in Aedes aegypti
  • the present invention uses the following methods to test the infection rate of dengue virus in Aedes aegypti in the iron-deficiency mouse model:
  • mice Four-week-old AG6 mice, weighing 15g, were randomly divided into 2 groups, namely the normal group and the iron-deficient mouse group, with 4 mice in each group, and the following treatments were performed:
  • Normal group four-week-old AG6 mice fed with normal feed for five weeks;
  • Iron-deficient mice group Four-week-old AG6 mice were fed iron-deficient feed for five weeks.
  • mice After the two groups of mice were fed for five weeks, on day 0, they were infected with dengue 2 virus through mouse footpad injection. From day 1 to day 5, clean Aedes aegypti mosquitoes (without dengue 2 infection) Virus clean Aedes aegypti) bites and sucks blood on mice, collects the blood-sucking Aedes aegypti and cultivates them.
  • Five groups of Aedes aegypti are obtained from normal group and iron-deficient mice, namely 1d.pi group, 2d.pi group, 3d.pi group, 4d.pi group and 5d.pi group.
  • the SYBR RT-PCR kit was used to detect dengue in Aedes aegypti using Actin of Aedes aegypti as a genetic reference 2
  • the relative expression of type virus genes According to the relative expression of dengue type 2 virus genes in Aedes aegypti in different groups, it is judged whether Aedes aegypti is infected with dengue virus.
  • the ratio of dengue virus expression/Actin expression i.e. relative expression
  • ⁇ 0.001 as the critical value for infection, that is, the ratio of dengue virus expression/Actin expression (i.e. relative expression) ⁇ 0.001
  • the primers used to detect Dengue 2 virus are as follows:
  • Upstream primer 5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’;
  • Downstream primer 5'-CAGATCTCTGATGAATAACCAACG-3'.
  • the primers of Actin gene used are as follows:
  • Upstream primer 5’-GAACACCCAGTCCTGCTGACA-3’;
  • Downstream primer 5'-TGCGTCATCTTCTCACGGTTAG-3'.
  • the dengue virus infection rates of the five groups of Aedes aegypti corresponding to the normal group and the iron-deficient mouse group are shown in Table 1 and Figure 2.
  • the results show that the five groups of Aedes aegypti in the iron-deficient mouse group (respectively labeled “ 1d.pi” “2d.pi” “3d.pi” “4d.pi” and “5d.pi”) have higher dengue virus infection rates than the corresponding five groups of Aedes aegypti in the normal group (in the figure respectively "1d.pi", “2d.pi”, “3d.pi”, “4d.pi”, and "5d.pi”) of the dengue virus infection rate.
  • the three groups of Aedes aegypti (indicated by "2d.pi” in the figure) ""3d.pi” and “4d.pi” means that the host's iron content has a significant impact on the susceptibility of Aedes aegypti to dengue virus.
  • Low-iron or iron-deficiency hosts can increase the The susceptibility of mosquitoes to dengue virus.
  • Table 1 The infection rate of dengue virus in Aedes aegypti in the iron-deficiency mouse model
  • N represents the total number of Aedes aegypti
  • n represents the number of Aedes aegypti infected by dengue virus
  • W represents the infection rate
  • Example 3 Iron supplementation of infected hosts can significantly inhibit the susceptibility of dengue virus in Aedes aegypti
  • the present invention uses the following method to test the infection rate of dengue virus in Aedes aegypti after iron supplementation to the infected host:
  • the four-week-old AG6 mice were fed iron-deficient feed for five weeks to obtain nine-week-old iron-deficient AG6 mice.
  • the serum iron of the mice fed for the third, fourth, and fifth weeks was measured. The results are shown in the figure As shown in 3, compared with the normal group of mice, the serum iron concentration of the mice was significantly reduced after being fed iron-deficient feed for five weeks, indicating that iron-deficient mice were constructed.
  • the nine-week-old iron-deficient AG6 mice in step 1 were injected with dengue 2 virus on each footpad, and then the nine-week-old iron-deficient AG6 mice infected with dengue virus, weighing 25g, were randomly divided into 2 groups , Namely the control group and the iron-supplemented group, each group has 4 animals, and the following injection treatments are carried out:
  • Control group Each nine-week-old AG6 mouse was injected with 0.01% normal saline, 50 ⁇ L per mouse, through the tail vein.
  • Iron supplementation group Each nine-week-old AG6 mouse was injected with 60 ⁇ g/mL ferric ammonium citrate solution through the tail vein, 50 ⁇ L per mouse.
  • mice in the control group and the iron-supplemented group after the above injection treatment were bitten and sucked blood by clean Aedes aegypti mosquitoes (clean Aedes aegypti not infected with Dengue 2 virus) every day from day one to day five (15 minutes after the tail vein injection on the first day, Aedes aegypti bites the mice), the blood-sucking Aedes aegypti were collected and cultured.
  • the control group and the iron supplementation group received five groups of Aedes aegypti, namely the 1d.pi group. , 2d.pi group, 3d.pi group, 4d.pi group and 5d.pi group, each group is divided into two groups (the first group and the second group).
  • mice Eight days after the first group of Aedes aegypti bit the mice, the midgut tissue of Aedes aegypti was isolated, the total RNA of the intestine was extracted, and reverse transcribed into cDNA.
  • the Actin of Aedes aegypti was used as the gene using SYBR RT-PCR kit
  • the internal control detects the relative expression level of the E gene of the dengue 2 virus in Aedes aegypti. According to the relative expression of dengue 2 virus E gene in Aedes aegypti in different groups, it is judged whether Aedes aegypti is infected with dengue virus.
  • the ratio of dengue virus expression/Actin expression (i.e. relative expression) ⁇ 0.001 as the critical value for infection, that is, the ratio of dengue virus expression/Actin expression (i.e. relative expression) ⁇ 0.001 Aedes aegypti successfully infected with dengue virus.
  • the primers used to detect Dengue 2 virus are as follows:
  • Upstream primer 5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’;
  • Downstream primer 5'-CAGATCTCTGATGAATAACCAACG-3'.
  • the primers of Actin gene used are as follows:
  • Upstream primer 5’-GAACACCCAGTCCTGCTGACA-3’;
  • Downstream primer 5'-TGCGTCATCTTCTCACGGTTAG-3'.
  • the dengue virus infection rates of the five groups of Aedes aegypti corresponding to the control group and the iron supplementation group are shown in Table 2 and Figure 4.
  • the results show that the five groups of Aedes aegypti in the iron supplementation group (respectively labeled "1d.pi” in the figure) "2d.pi", “3d.pi”, “4d.pi”, and “5d.pi” indicate that the dengue virus infection rate in the midgut is lower than the corresponding five groups of Aedes aegypti in the control group (in the figure, respectively, "1d.
  • Table 2 The infection rate of dengue virus in the intestinal tissue of Aedes aegypti after iron supplementation in the infected host
  • N represents the total number of Aedes aegypti
  • n represents the number of Aedes aegypti infected by dengue virus
  • W represents the infection rate
  • Aedes aegypti Fourteen days after the second group of Aedes aegypti bit the mice, the salivary glands of Aedes aegypti were isolated and the total RNA of the salivary glands was extracted and reverse transcribed into cDNA.
  • the Actin of Aedes aegypti was used as a gene reference using SYBR RT-PCR kit Detect the relative expression level of the dengue 2 virus gene in Aedes aegypti. According to the relative expression of dengue type 2 virus genes in Aedes aegypti in different groups, it is judged whether Aedes aegypti is infected with dengue virus.
  • the ratio of dengue virus expression/Actin expression (i.e. relative expression) ⁇ 0.001 as the critical value for infection, that is, the ratio of dengue virus expression/Actin expression (i.e. relative expression) ⁇ 0.001 Aedes aegypti successfully infected with dengue virus.
  • the primers used to detect Dengue 2 virus are as follows:
  • Upstream primer 5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’;
  • Downstream primer 5'-CAGATCTCTGATGAATAACCAACG-3'.
  • the primers of Actin gene used are as follows:
  • Upstream primer 5’-GAACACCCAGTCCTGCTGACA-3’;
  • Downstream primer 5'-TGCGTCATCTTCTCACGGTTAG-3'.
  • the salivary dengue virus infection rates of the five groups of Aedes aegypti corresponding to the control group and the iron supplement group are shown in Table 3 and Figure 5. Each open dot represents one Aedes aegypti salivary gland.
  • Table 3 The infection rate of dengue virus in the salivary glands of Aedes aegypti after iron supplementation in the infected host
  • N represents the total number of Aedes aegypti
  • n represents the number of Aedes aegypti infected by dengue virus
  • W represents the infection rate
  • Aedes aegypti bites dengue virus infected hosts with different iron states and presents significantly different viral infection rates.
  • the susceptibility of Aedes aegypti to dengue virus is significantly negatively correlated with the iron status of the host’s blood, that is, the bite Infected hosts with low iron status are more susceptible to virus infection.
  • the establishment of iron-deficiency mouse models confirmed that iron supplementation (ferric ammonium citrate) can effectively reduce the susceptibility of Aedes aegypti to dengue virus. Therefore, iron-containing substances (ferric ammonium citrate) can Reduce the ability of Aedes aegypti to carry the virus and block the spread of the virus in nature.

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Abstract

含铁物质在制备抑制登革病毒传播和/或抑制蚊虫对登革病毒的易感性的产品中的应用。埃及伊蚊叮咬不同铁状态的被登革病毒感染的宿主出现不同的病毒感染率，埃及伊蚊对登革病毒的易感性与宿主血液的铁状态呈负相关性。对缺铁小鼠模型进行补铁可降低埃及伊蚊引发登革病毒的易感性，表明含铁物质可降低埃及伊蚊携带病毒的能力和阻断病毒的传播。

Description

含铁物质在制备抑制登革病毒传播的产品中的应用 技术领域
本发明涉及含铁物质在制备抑制登革病毒传播的产品中的应用。
背景技术
埃及伊蚊是一类以吸血获取和传播病毒的昆虫，是引发“登革热”的祸首。“登革热”是热带和亚热带地区流行的以蚊虫为媒介的急性传染病，具有传播快、发病率高等特点，由蚊虫所传播的病毒会表现出脑炎、脑膜炎、出血热等临床症状，每年导致上亿人次的感染以及数十万的死亡病例，对世界公共卫生造成严重的危害。
补铁是一种对缺铁、低铁人群普遍适用的医学方法，但目前为止还没有关于补铁能有效降低埃及伊蚊对登革病毒的易感性的相关报道。
发明公开
本发明所要解决的技术问题为如何抑制登革病毒的传播。
为解决上述技术问题，本发明首先公开了含铁物质在制备抑制登革病毒传播的产品中的应用。
本发明进一步公开了含铁物质在制备抑制蚊虫对登革病毒的易感性的产品中的应用。
本发明还提供了一种抑制登革病毒传播的方法。
本发明抑制登革病毒传播的方法，包括给被登革病毒感染的宿主施用上述含铁物质，从而抑制登革病毒的传播。
本发明进一步还提供了一种抑制蚊虫对登革病毒的易感性的方法，包括给被登革病毒感染的宿主施用上述含铁物质，从而抑制蚊虫对登革病毒的易感性。
上文中，所述含铁物质的活性成分为含铁化合物；所述含铁物质可以为纯净物或混合物；具体的，所述含铁物质可以为补铁剂。
上文中，所述含铁物质的活性成分可为柠檬酸铁铵。
上文中，所述产品可为食品、药品或保健品等等。
所述产品除含有含铁化合物外，还可含有适宜的载体或赋形剂。这里的载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等)。其中优选的是水溶性载体材料。使用这些材料可以制成多种剂型，包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关 于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将单位给药剂型制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将单位给药剂型制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将单位给药剂型制成注射用制剂，如溶液剂、乳剂、冻干粉针剂和混悬剂，可以使用本领域常用的所有稀释剂，例如，水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。使用上述剂型可以经注射给药，包括皮下注射、静脉注射、肌肉注射和腔内注射等；腔道给药，如经直肠和阴道；呼吸道给药，如经鼻腔；粘膜给药。
上文中，所述蚊虫为埃及伊蚊或其他具有传播病毒能力的蚊虫。
上文中，所述登革病毒为登革2型病毒(dengue virus type-2,DENV-2)。
上文中，所述被登革病毒感染的宿主可为缺铁或低铁动物，可为哺乳动物，如人和鼠。
附图说明
图1为柠檬酸铁铵对登革病毒在埃及伊蚊体内的感染率的影响；每个空心圆点代表一只埃及伊蚊。
图2为缺铁小鼠对登革病毒在埃及伊蚊体内的感染率的影响；每个空心圆点代表一只埃及伊蚊。
图3为缺铁小鼠与正常小鼠的血清铁测定，每个空心圆代表一只小鼠。
图4为缺铁小鼠补铁对埃及伊蚊肠组织的登革病毒感染率的影响；每个空心 圆点代表一只埃及伊蚊。
图5为缺铁小鼠补铁对埃及伊蚊唾液腺的登革病毒感染率的影响；每个空心圆点代表一只埃及伊蚊。
实施发明的最佳方式
下面结合具体实施方式对本发明进行进一步的详细描述，给出的实施例仅为了阐明本发明，而不是为了限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中埃及伊蚊(Aedes aegypti)在文献“Colpitts TM et al.Alterations in the Aedes aegypti Transcriptome during Infection with West Nile,Dengue and Yellow Fever Viruses.2011,PloSPathog 7(9):e1002189.”中公开过，公众可从清华大学医学院获得。
下述实施例中登革2型病毒(dengue virus type-2,DENV-2)的New Guinea C株在文献“Liu et al.Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes.2016,Nat Microbiol 1(9):16087.”中公开过，公众可从清华大学医学院获得。
下述实施例中柠檬酸铁铵购买于Sigma公司，产品目录号为F5879。
下述实施例中正常饲料购买于南通特洛菲饲料科技有限公司，货号：TP0306C。
下述实施例中缺铁饲料购买于南通特洛菲饲料科技有限公司，货号：TP0306。
实施例1、体外膜饲喂系统饲喂柠檬酸铁铵抑制登革病毒在埃及伊蚊体内的易感性
体外膜饲喂系统饲喂柠檬酸铁铵可以降低埃及伊蚊对登革病毒的感染率，具体试验如下：
1、将埃及伊蚊分成4组，即对照组、25μM FAC组、50μM FAC组和150μM FAC组，分别进行如下处理：
对照组：每只埃及伊蚊通过体外膜饲喂系统饲喂人抗凝全血样本和登革2型病毒(DENV-2)上清(1:1体积比)的混合液；
25μM FAC组：每只埃及伊蚊通过体外膜饲喂系统饲喂含有柠檬酸铁铵(FAC)的人抗凝全血样本和登革2型病毒(DENV-2)上清(1:1体积比)的混合液，所述柠檬酸铁铵在所述混合液中的浓度为25μM。
50μM FAC组：每只埃及伊蚊通过体外膜饲喂系统饲喂含有柠檬酸铁铵(FAC)的人抗凝全血样本和登革2型病毒(DENV-2)上清(1:1体积比)的混合液，所述柠檬酸铁铵在所述混合液中的浓度为50μM。
150μM FAC组：每只埃及伊蚊通过体外膜饲喂系统饲喂含有柠檬酸铁铵(FAC)的人抗凝全血样本和登革2型病毒(DENV-2)上清(1:1体积比)的混合液，所 述柠檬酸铁铵在所述混合液中的浓度为150μM。
2、饲喂八天后，提取埃及伊蚊的总RNA，反转录为cDNA，利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革2型病毒基因的相对表达量。根据不同组别中埃及伊蚊体内的登革2型病毒基因的相对表达量判断埃及伊蚊是否感染登革病毒。以登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001作为是否感染的临界值，即登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001表示埃及伊蚊成功感染登革病毒。
其中，用于检测登革2型病毒的引物如下：
上游引物：5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’(序列1)；
下游引物：5’-CAGATCTCTGATGAATAACCAACG-3’(序列2)。
所用Actin基因的引物如下：
上游引物：5’-GAACACCCAGTCCTGCTGACA-3’(序列3)；
下游引物：5’-TGCGTCATCTTCTCACGGTTAG-3’(序列4)。
对照组(图中以“对照组”表示)、25μM FAC组(图中以“25μM FAC”表示)、50μM FAC组(图中以“50μM FAC”表示)和150μM FAC组(图中以“150μM FAC”表示)的埃及伊蚊体内的登革2型病毒的感染情况如图1所示。结果显示：随着蚊虫饲喂柠檬酸铁铵的浓度逐渐上升，埃及伊蚊体内的登革2型病毒感染率出现显著下降，表明埃及伊蚊饲喂柠檬酸铁铵可以降低登革2型病毒在埃及伊蚊体内的病毒感染效率。
实施例2、缺铁小鼠模型显著提高登革病毒在埃及伊蚊体内的易感性
在埃及伊蚊吸血过程中宿主体内的病毒颗粒和大量血液进入埃及伊蚊体内，因此，本发明采用如下方法进行缺铁小鼠模型对登革病毒在埃及伊蚊体内的感染率试验：
一、制备正常对照小鼠和缺铁AG6小鼠
将四周龄AG6小鼠，体重是15g，随机分成2组，即正常组和缺铁小鼠组，每组4只，分别进行如下处理：
正常组：四周龄AG6小鼠饲喂正常饲料五周；
缺铁小鼠组：四周龄AG6小鼠饲喂将缺铁饲料五周。
二、两组小鼠饲喂五周之后，第0天通过小鼠足垫注射感染登革2型病毒，从第一天到第五天每天由干净的埃及伊蚊(无感染登革2型病毒的干净埃及伊蚊)对小鼠进行叮咬吸血，收集吸血完毕的埃及伊蚊进行培养，正常组和缺铁小鼠均得到五组埃及伊蚊，即1d.p.i.组、2d.p.i.组、3d.p.i.组、4d.p.i.组和5d.p.i.组。
三、埃及伊蚊叮咬小鼠八天后，提取埃及伊蚊的总RNA，反转录为cDNA，利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革2型病毒基因的相对表达量。根据不同组别中埃及伊蚊体内的登革2型 病毒基因的相对表达量判断埃及伊蚊是否感染登革病毒。以登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001作为是否感染的临界值，即登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001表示埃及伊蚊成功感染登革病毒。
其中，用于检测登革2型病毒的引物如下：
上游引物：5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’；
下游引物：5’-CAGATCTCTGATGAATAACCAACG-3’。
所用Actin基因的引物如下：
上游引物：5’-GAACACCCAGTCCTGCTGACA-3’；
下游引物：5’-TGCGTCATCTTCTCACGGTTAG-3’。
正常组和缺铁小鼠组对应的五组埃及伊蚊的登革病毒感染率如表1和图2所示，结果显示：缺铁小鼠组中五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革病毒感染率均高于正常组中对应的五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革病毒感染率，其中，三组埃及伊蚊(图中分别以“2d.p.i.”“3d.p.i.”“4d.p.i.”表示)达到了显著性的水平，表明宿主的铁含量对埃及伊蚊对登革病毒的易感性造成显著影响，低铁或缺铁宿主可提高埃及伊蚊对登革病毒的易感性。
表1 缺铁小鼠模型对登革病毒在埃及伊蚊的感染率情况
Figure PCTCN2019120582-appb-000001
注：N表示埃及伊蚊总数，n表示被登革病毒感染的埃及伊蚊数，W表示感染率
实施例3、对感染宿主进行补铁可显著抑制登革病毒在埃及伊蚊体内的易感性
在埃及伊蚊吸血过程中宿主体内的病毒颗粒和大量血液进入埃及伊蚊体内，因此，本发明采用如下方法进行对感染宿主补铁后对登革病毒在埃及伊蚊体内的感染率试验：
一、制备缺铁AG6小鼠
将四周龄AG6小鼠饲喂缺铁饲料五周，得到九周龄缺铁AG6小鼠，对饲喂第三周、第四周和第五周的小鼠的血清铁进行测定，结果如图3所示，与正常组小鼠相比，饲喂缺铁饲料五周后小鼠血清铁浓度明显降低，说明构建了缺铁小鼠。
二、对步骤一的九周龄缺铁AG6小鼠每只足垫注射感染登革2型病毒，随后将感染登革病毒的九周龄缺铁AG6小鼠，体重是25g，随机分成2组，即对照组和补铁组，每组4只，分别进行如下注射处理：
对照组：每只九周龄AG6小鼠通过尾静脉注射质量百分含量为0.01％生理盐水，每只小鼠50μL。
补铁组：每只九周龄AG6小鼠通过尾静脉注射含量为60μg/mL柠檬酸铁铵溶液，每只小鼠50μL。
将经过上述注射处理的对照组和补铁组小鼠，从第一天到第五天每天由干净的埃及伊蚊(无感染登革2型病毒的干净埃及伊蚊)对小鼠进行叮咬吸血(第一天尾静脉注射15分钟之后，埃及伊蚊对小鼠进行叮咬)，收集吸血完毕的埃及伊蚊进行培养，对照组和补铁组分别得到五组埃及伊蚊，即1d.p.i.组、2d.p.i.组、3d.p.i.组、4d.p.i.组和5d.p.i.组，每组分为两小组(第一小组和第二小组)。
三、第一小组埃及伊蚊叮咬小鼠八天后，分离埃及伊蚊的中肠组织，提取肠的总RNA，反转录为cDNA，利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革2型病毒E基因的相对表达量。根据不同组别中埃及伊蚊体内的登革2型病毒E基因的相对表达量判断埃及伊蚊是否感染登革病毒。以登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001作为是否感染的临界值，即登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001表示埃及伊蚊成功感染登革病毒。
其中，用于检测登革2型病毒的引物如下：
上游引物：5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’；
下游引物：5’-CAGATCTCTGATGAATAACCAACG-3’。
所用Actin基因的引物如下：
上游引物：5’-GAACACCCAGTCCTGCTGACA-3’；
下游引物：5’-TGCGTCATCTTCTCACGGTTAG-3’。
对照组和补铁组对应的五组埃及伊蚊的登革病毒感染率如表2和图4所示，结果显示：补铁组中五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)中肠的登革病毒感染率均低于对照组对应的五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革病毒感染率，其中，三组埃及伊蚊(图中分别以“2d.p.i.”“3d.p.i.”“4d.p.i.”表示)达到了显著性的水平，表明对感染宿主进行补铁可显著抑制埃及伊蚊对登革病毒的易感性，从而达到防控登革病毒传播的目的。
表2 感染宿主补铁后对登革病毒在埃及伊蚊肠组织的感染率情况
Figure PCTCN2019120582-appb-000002
Figure PCTCN2019120582-appb-000003
注：N表示埃及伊蚊总数，n表示被登革病毒感染的埃及伊蚊数，W表示感染率
四、第二小组埃及伊蚊叮咬小鼠十四天后，分离埃及伊蚊的唾液腺，提取唾液腺的总RNA，反转录为cDNA，利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革2型病毒基因的相对表达量。根据不同组别中埃及伊蚊体内的登革2型病毒基因的相对表达量判断埃及伊蚊是否感染登革病毒。以登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001作为是否感染的临界值，即登革病毒表达量/Actin的表达量的比值(即相对表达量)≧0.001表示埃及伊蚊成功感染登革病毒。
其中，用于检测登革2型病毒的引物如下：
上游引物：5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’；
下游引物：5’-CAGATCTCTGATGAATAACCAACG-3’。
所用Actin基因的引物如下：
上游引物：5’-GAACACCCAGTCCTGCTGACA-3’；
下游引物：5’-TGCGTCATCTTCTCACGGTTAG-3’。
对照组和补铁组对应的五组埃及伊蚊的唾液登革病毒感染率如表3和图5所示，每个空心圆点代表一只埃及伊蚊唾液腺。结果显示补铁组中五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)唾液腺的登革病毒感染率均显著低于对照组对应的五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革病毒感染率，其中，三组埃及伊蚊(图中分别以“2d.p.i.”“3d.p.i.”“4d.p.i.”表示)达到了显著性的水平，表明对感染宿主进行补铁可显著抑制埃及伊蚊对登革病毒的传播能力。
表3 感染宿主补铁后对登革病毒在埃及伊蚊唾液腺的感染率情况
Figure PCTCN2019120582-appb-000004
注：N表示埃及伊蚊总数，n表示被登革病毒感染的埃及伊蚊数，W表示感染率
以上结果表明，对被登革病毒感染的宿主进行补铁能有效抑制蚊虫对登革 病毒传播能力和蚊虫对登革病毒的易感性。
工业应用
本发明埃及伊蚊叮咬不同铁状态的登革病毒感染宿主出现显著差异的病毒感染率，埃及伊蚊对登革病毒的易感性与宿主血液的铁状态呈显著负相关性，即埃及伊蚊叮咬低铁状态的感染宿主更易感染病毒。通过建立缺铁小鼠模型证实，对缺铁小鼠模型进行补铁(柠檬酸铁铵)可有效降低埃及伊蚊引发登革病毒的易感性，因此，含铁物质(柠檬酸铁铵)可降低埃及伊蚊携带病毒的能力和阻断病毒在自然界中的传播。

Claims (10)

  1. 含铁物质在制备抑制登革病毒传播和/或抑制蚊虫对登革病毒的易感性的产品中的应用。
  2. 根据权利要求1所述的应用，其特征在于：所述含铁物质的活性成分为含铁化合物。
  3. 根据权利要求2所述的应用，其特征在于：所述含铁物质为补铁剂。
  4. 根据权利要求1所述的应用，其特征在于：所述含铁物质的活性成分为柠檬酸铁铵。
  5. 根据权利要求1所述的应用，其特征在于：所述产品为药品、食品或保健品。
  6. 根据权利要求1所述的应用，其特征在于：所述蚊虫为埃及伊蚊或其他具有传播病毒能力的蚊虫。
  7. [根据细则91更正 23.12.2019]　
    一种抑制登革病毒传播的方法，其特征在于：所述方法包括给被登革病毒感染的宿主施用权利要求1-6任一中所述的含铁物质，从而抑制登革病毒的传播。
  8. [根据细则91更正 23.12.2019]　
    根据权利要求7所述的方法，其特征在于：所述被登革病毒感染的宿主为缺铁或低铁动物。
  9. [根据细则91更正 23.12.2019]　
    一种抑制蚊虫对登革病毒的易感性的方法，其特征在于：所述方法包括给被登革病毒感染的宿主施用权利要求1-6任一中所述的含铁物质，从而抑制蚊虫对登革病毒的易感性。
  10. [根据细则91更正 23.12.2019]　
    根据权利要求9所述的方法，其特征在于：所述被登革病毒感染的宿主为缺铁或低铁动物。
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