vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ18.381vavilov-1548Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSАССОЦИАЦИЯ ПОЛИМОРФИЗМА ГЕНОВ 2′-5′-ОЛИГОАДЕНИЛАТСИНТЕТАЗ С УРОВНЕМ ГУМОРАЛЬНОГО ИММУННОГО ОТВЕТА ПОСЛЕ ВАКЦИНАЦИИ ПРОТИВ КЛЕЩЕВОГО ЭНЦЕФАЛИТАASSOCIATION BETWEEN POLYMORPHISMS IN GENES ENCODING 2′-5′-OLIGOADENYLATE SYNTHETASES AND THE HUMORAL IMMUNE RESPONSE UPON VACCINATION AGAINST TICK-BORNE ENCEPHALITISЮдинН. С.YudinN. S.yudin@bionet.nsc.ruИгошинА. В.IgoshinA. V.

Новосибирск

Novosibirsk

ЛутоваС. Л.LutovaS. L.ГонЯ.GonYa.ВоеводаМ. И.VoevodaM. I.БелявскаяВ. А.BelyavskayaV. A.

Новосибирская область,  р. п. Кольцово

Novosibirsk region, Koltsovo

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университет; Научно-исследовательский институт терапии и профилактической медицины – филиал Федерального исследовательского центра Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics SB RAS; Novosibirsk State University; Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics SB RASRussian FederationГосударственное бюджетное учреждение здравоохранения Новосибирской области «Городская поликлиника № 14»РоссияState Budgetary Health Care Institution of the Novosibirsk Region “City Hospital № 14”Russian FederationНовосибирский национальный исследовательский государственный университетРоссияNovosibirsk State UniversityRussian FederationГосударственный научный центр вирусологии и биотехнологии «Вектор» Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человекаРоссияState Research Center of Virology and Biotechnology “Vector” of the Federal Service for Surveillance in Consumer Rights Protection and Human Well-beingRussian Federation201804072018224445451Copyright © Юдин Н.С., Игошин А.В., Лутова С.Л., Гон Я., Воевода М.И., Белявская В.А., 20182018Юдин Н.С., Игошин А.В., Лутова С.Л., Гон Я., Воевода М.И., Белявская В.А.Yudin N.S., Igoshin A.V., Lutova S.L., Gon Y., Voevoda M.I., Belyavskaya V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1548

Вакцинация является эффективным средством профилактики клещевого энцефалита, формирующим активный иммунитет. Однако избыточная иммунизация при вакцинации неоправданна с точки зрения экономики и медицинской этики. Одним из подходов к индивидуализации вакцинации может быть подбор доз вакцины в зависимости от ожидаемого уровня иммунного ответа пациента. Поэтому возникает необходимость разработки методов оценки потенциального уровня иммунологических реакций человека до проведения вакцинации. Цель работы – поиск возможных ассоциаций однонуклеотидных полиморфных маркеров (ОНП) в генах OAS2 и OAS3, для которых ранее была найдена корреляция с развитием тяжелых форм клещевого энцефалита, а также с образованием антител и  цитокинов после вакцинации против клещевого энцефалита. В исследовании приняли участие 97 добровольцев обоего пола, ранее не вакцинированных и не имевших контактов с клещами. Через один месяц после иммунизации вакциной « ЭнцеВир» у них брали пробы венозной крови. Анализировали уровни специфических антител IgG против вируса клещевого энцефалита и интерлейкина 4 (ИЛ-4). Генотипировали ОНП rs2285932, rs2072136, rs1293762, rs15895 и rs1732778 в генах 2’-5’-олигоаденилатсинтетаз OAS2 и OAS3. Выработка антител в ответ на введение вакцины была достоверно ассоциирована с ОНП rs1732778 в регуляторном районе гена OAS2. Этот показатель оказался существенно выше у людей с гетерозиготным генотипом G/A , чем у субъектов с гомозиготными генотипами G/G и A/A. Индивиды-носители аллеля А в составе генотипов G/A и A/A этого же ОНП имели сниженный уровень ИЛ-4 по сравнению с гомозиготными индивидами G/G. Полученные нами результаты свидетельствуют о том, что ОНП rs1732778 в регуляторной области гена OAS2 ассоциирован с образованием противовирусных антител IgG и уровнем ИЛ-4 после вакцинации. По-видимому, генетический полиморфизм в гене OAS2 следует принимать во внимание при индивидуализации вакцинопрофилактики клещевого энцефалита.

Vaccination forms active immunity and represents an effective way of preventing tick-borne encephalitis (TBE). However, excessive vaccination is unjustified in terms of economics and medical ethics. One of the individualized approaches to vaccines is the selection of vaccine doses depending on the expected levels of immune response. Therefore, there is a need for new methods for assessing potential human immune responses prior to vaccination. The aim of this study was to determine possible association between single nucleotide polymorphisms (SNPs) located within OAS2 and OAS3 genes, which have been previously associated with the development of severe forms of TBE, and the formation of antibodies and cytokines upon vaccination against TBE. The study involved 97 volunteers of both sexes who had not previously been vaccinated against TBE and had no contact with ticks. Venous blood samples were collected one month after vaccination against TBE using the EnceVir vaccine. Levels of specific IgG antibodies against tick-borne encephalitis virus and interleukin 4 (IL-4) were analyzed. Genomic DNA samples were genotyped for the SNPs rs2285932, rs2072136, rs1293762, rs15895 and rs1732778 in genes encoding 2’-5’-oligoadenylate synthetases OAS2 and OAS3. Antibody production in response to vaccine administration was significantly associated with SNP rs1732778 in the regulatory region of the OAS2 gene. This indicator was significantly higher in people with heterozygous genotypes G/A as compared to people with homozygous genotypes G/G and A/A. Carriers of the A allele (G/A or A/A genotypes) of the same SNP had reduced IL-4 levels as compared to the homozygous G/G individuals. Thus, the data obtained indicate that SNP rs1732778 in the regulatory region of the OAS2 gene correlates with the formation of antiviral IgG antibodies and changes in IL-4 levels upon vaccination. Evidently, the genetic polymorphism in OAS2 gene should be considered when performing individualized TBE vaccinations.

клещевой энцефалитвакцинацияIgG антителагенOAS2OAS3однонуклеотидный полиморфизмассоциацияtick-borne encephalitisvaccinationIgG antibodiesgeneOAS2OAS3single nucleotide polymorphismassociationRussian Science Foundation grant (project 16-15-00127)ReferencesAlagarasu K., Honap T., Damle I.M., Mulay A.P., Shah P.S., Cecilia D. Polymorphisms in the oligoadenylate synthetase gene cluster and its association with clinical outcomes of dengue virus infection. Infect. Genet. Evol. 2013;14:390-395. DOI 10.1016/j.meegid.2012.12.021.Alagarasu K., Honap T., Damle I.M., Mulay A.P., Shah P.S., Cecilia D. Polymorphisms in the oligoadenylate synthetase gene cluster and its association with clinical outcomes of dengue virus infection. Infect. Genet. Evol. 2013;14:390-395. DOI 10.1016/j.meegid.2012.12.021.Allen I.C., Scull M.A., Moore C.B., Holl E.K., McElvania-TeKippe E., Taxman D.J., Guthrie E.H., Pickles R.J., Ting J.P. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30:556-565.Allen I.C., Scull M.A., Moore C.B., Holl E.K., McElvania-TeKippe E., Taxman D.J., Guthrie E.H., Pickles R.J., Ting J.P. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30:556-565.Barkhash A.V., Babenko V.N., Kobzev V.F., Romashchenko A.G., Voe voda M.I. Polymorphism in the human 2′-5′-oligoadenylate synthetase genes (OAS), associated with predisposition to severe forms of tick-borne ence phalitis, in populations from North Eurasia. Molekulyarnaya Bio lo giya = Molecular Biology (Moscow). 2010;44:985-993.(in Russian)Barkhash A.V., Babenko V.N., Kobzev V.F., Romashchenko A.G., Voe voda M.I. Polymorphism in the human 2′-5′-oligoadenylate synthetase genes (OAS), associated with predisposition to severe forms of tick-borne ence phalitis, in populations from North Eurasia. Molekulyarnaya Bio lo giya = Molecular Biology (Moscow). 2010;44:985-993.(in Russian)Barkhash A.V., Perelygin A.A., Babenko V.N., Myasnikova N.G., Pilipenko P.I., Romaschenko A.G., Voevoda M.I., Brinton M.A. Variability in the 2′-5′-oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease. J. Infect. Dis. 2010;202(12):1813-1818. DOI 10.1086/657418.Barkhash A.V., Perelygin A.A., Babenko V.N., Myasnikova N.G., Pilipenko P.I., Romaschenko A.G., Voevoda M.I., Brinton M.A. Variability in the 2′-5′-oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease. J. Infect. Dis. 2010;202(12):1813-1818. DOI 10.1086/657418.Bigham A.W., Buckingham K.J., Husain S., Emond M.J., Bofferding K.M., Gildersleeve H., Rutherford A., Astakhova N.M., Perelygin A.A., Busch M.P., Murray K.O., Sejvar J.J., Green S., Kriesel J., Brinton M.A., Bamshad M. Host genetic risk factors for West Nile virus infection and disease progression. PLoS One. 2011;6(9):e24745. DOI 10.1371/journal.pone.0024745.Bigham A.W., Buckingham K.J., Husain S., Emond M.J., Bofferding K.M., Gildersleeve H., Rutherford A., Astakhova N.M., Perelygin A.A., Busch M.P., Murray K.O., Sejvar J.J., Green S., Kriesel J., Brinton M.A., Bamshad M. Host genetic risk factors for West Nile virus infection and disease progression. PLoS One. 2011;6(9):e24745. DOI 10.1371/journal.pone.0024745.Bilalova G.P. Issues of the practical use of Encevir vaccine. Sibirskiy Medi tsinskiy Zhurnal = Siberian Medical Journal. 2009;2:86-91. (in Russian)Bilalova G.P. Issues of the practical use of Encevir vaccine. Sibirskiy Medi tsinskiy Zhurnal = Siberian Medical Journal. 2009;2:86-91. (in Russian)Danial-Farran N., Eghbaria S., Schwartz N., Kra-Oz Z., Bisharat N. Genetic variants associated with susceptibility of Ashkenazi Jews to West Nile virus infection. Epidemiol. Infect. 2015;143:857-863. DOI 10.1017/S0950268814001290.Danial-Farran N., Eghbaria S., Schwartz N., Kra-Oz Z., Bisharat N. Genetic variants associated with susceptibility of Ashkenazi Jews to West Nile virus infection. Epidemiol. Infect. 2015;143:857-863. DOI 10.1017/S0950268814001290.Dugan J.W., Albor A., David L., Fowlkes J., Blackledge M.T., Martin T.M., Planck S.R., Rosenzweig H.L., Rosenbaum J.T., Davey M.P. Nucleotide oligomerization domain-2 interacts with 2′-5′-oligoadenylate synthetase type 2 and enhances RNase-L function in THP-1 cells. Mol. Immunol. 2009;47(2-3):560-566. DOI 10.1016/j.molimm.2009.09.025.Dugan J.W., Albor A., David L., Fowlkes J., Blackledge M.T., Martin T.M., Planck S.R., Rosenzweig H.L., Rosenbaum J.T., Davey M.P. Nucleotide oligomerization domain-2 interacts with 2′-5′-oligoadenylate synthetase type 2 and enhances RNase-L function in THP-1 cells. Mol. Immunol. 2009;47(2-3):560-566. DOI 10.1016/j.molimm.2009.09.025.Gadani S.P., Cronk J.C., Norris G.T., Kipnis J. IL-4 in the brain: a cytokine to remember. J. Immunol. 2012;189:4213-4219. DOI 10.4049/jimmunol.1202246.Gadani S.P., Cronk J.C., Norris G.T., Kipnis J. IL-4 in the brain: a cytokine to remember. J. Immunol. 2012;189:4213-4219. DOI 10.4049/jimmunol.1202246.Geha R.S., Jabara H.H., Brodeur S.R. The regulation of immunoglobulin E class-switch recombination. Nat. Rev. Immunol. 2003;3: 721-732.Geha R.S., Jabara H.H., Brodeur S.R. The regulation of immunoglobulin E class-switch recombination. Nat. Rev. Immunol. 2003;3: 721-732.Gordon S. Alternative activation of macrophages. Nat. Rev. Immunol. 2003;3:23-35Gordon S. Alternative activation of macrophages. Nat. Rev. Immunol. 2003;3:23-35Gröndahl-Yli-Hannuksela K., Vahlberg T., Ilonen J., Mertsola J., He Q. Polymorphism of IL-10 gene promoter region: association with T cell proliferative responses after acellular pertussis vaccination in adults. Immunogenetics. 2016;68:733-741. DOI 10.1007/s00251016-0923-0.Gröndahl-Yli-Hannuksela K., Vahlberg T., Ilonen J., Mertsola J., He Q. Polymorphism of IL-10 gene promoter region: association with T cell proliferative responses after acellular pertussis vaccination in adults. Immunogenetics. 2016;68:733-741. DOI 10.1007/s00251016-0923-0.Haralambieva I.H., Dhiman N., Ovsyannikova I.G., Vierkant R.A., Pankratz V.S., Jacobson R.M., Poland G.A. 2′-5′-Oligoadenylate synthetase single-nucleotide polymorphisms and haplotypes are associated with variations in immune responses to rubella vaccine. Hum. Immunol. 2010;71:383-391. DOI 10.1016/j.humimm.2010.01.004.Haralambieva I.H., Dhiman N., Ovsyannikova I.G., Vierkant R.A., Pankratz V.S., Jacobson R.M., Poland G.A. 2′-5′-Oligoadenylate synthetase single-nucleotide polymorphisms and haplotypes are associated with variations in immune responses to rubella vaccine. Hum. Immunol. 2010;71:383-391. DOI 10.1016/j.humimm.2010.01.004.Hovanessian A.G., Justesen J. The human 2′-5′oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2′-5′ instead of 3′-5′ phosphodiester bond formation. Biochimie. 2007;89: 779-788.Hovanessian A.G., Justesen J. The human 2′-5′oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2′-5′ instead of 3′-5′ phosphodiester bond formation. Biochimie. 2007;89: 779-788.Ierusalimsky A.P. Tick-Borne Encephalitis: Manual for Physicians. Novosibirsk: State Medical Academy Publ., 2001. (in Russian)Ierusalimsky A.P. Tick-Borne Encephalitis: Manual for Physicians. Novosibirsk: State Medical Academy Publ., 2001. (in Russian)Imran M., Manzoor S., Khattak N.M., Tariq M., Khalid M., Javed F., Bhatti S. Correlation of OAS1 gene polymorphism at exon 7 splice accepter site with interferon-based therapy of HCV infection in Pakistan. Viral Immunol. 2014;27:105-111. DOI 10.1089/vim.2013.0107.Imran M., Manzoor S., Khattak N.M., Tariq M., Khalid M., Javed F., Bhatti S. Correlation of OAS1 gene polymorphism at exon 7 splice accepter site with interferon-based therapy of HCV infection in Pakistan. Viral Immunol. 2014;27:105-111. DOI 10.1089/vim.2013.0107.Kristiansen H., Gad H.H., Eskildsen-Larsen S., Despres P., Hartmann R. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J. Interferon Cytokine Res. 2011;31:41-47. DOI 10.1089/jir.2010.0107.Kristiansen H., Gad H.H., Eskildsen-Larsen S., Despres P., Hartmann R. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J. Interferon Cytokine Res. 2011;31:41-47. DOI 10.1089/jir.2010.0107.Lim J.K., Lisco A., McDermott D.H., Huynh L., Ward J.M., Johnson B., Johnson H., Pape J., Foster G.A., Krysztof D., Follmann D., Stramer S.L., Margolis L.B., Murphy P.M. Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLoS Pathog. 2009;5:e1000321. DOI 10.1371/journal.ppat.1000321.Lim J.K., Lisco A., McDermott D.H., Huynh L., Ward J.M., Johnson B., Johnson H., Pape J., Foster G.A., Krysztof D., Follmann D., Stramer S.L., Margolis L.B., Murphy P.M. Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLoS Pathog. 2009;5:e1000321. DOI 10.1371/journal.ppat.1000321.Linnik J.E., Egli A. Impact of host genetic polymorphisms on vaccine induced antibody response. Hum. Vaccin. Immunother. 2016;12:907915. DOI 10.1080/21645515.2015.1119345.Linnik J.E., Egli A. Impact of host genetic polymorphisms on vaccine induced antibody response. Hum. Vaccin. Immunother. 2016;12:907915. DOI 10.1080/21645515.2015.1119345.Lutova S.L., Tumanov Yu.V., Voevoda M.I., Belyavskaya V.A. Tickborne encephalitis and vaccines: genetic and physiological factors influencing the functional activity of specific antibodies. Proceedings of the Scientific and Practical Conference. Novosibirsk, 2016;191-193. (in Russian)Lutova S.L., Tumanov Yu.V., Voevoda M.I., Belyavskaya V.A. Tickborne encephalitis and vaccines: genetic and physiological factors influencing the functional activity of specific antibodies. Proceedings of the Scientific and Practical Conference. Novosibirsk, 2016;191-193. (in Russian)Meduni tsin N.V. Vaccinology. Moscow: Triada-Х Publ., 2004. (in Russian)Meduni tsin N.V. Vaccinology. Moscow: Triada-Х Publ., 2004. (in Russian)Ogura Y., Inohara N., Benito A., Chen F.F., Yamaoka S., Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J. Biol. Chem. 2001;276:4812-4818. DOI 10.1074/jbc.M008072200.Ogura Y., Inohara N., Benito A., Chen F.F., Yamaoka S., Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J. Biol. Chem. 2001;276:4812-4818. DOI 10.1074/jbc.M008072200.Poland G.A., Kennedy R.B., Ovsyannikova I.G. Vaccinomics and personalized vaccinology: is science leading us toward a new path of directed vaccine development and discovery? PLoS Pathog. 2011;7:e1002344.Poland G.A., Kennedy R.B., Ovsyannikova I.G. Vaccinomics and personalized vaccinology: is science leading us toward a new path of directed vaccine development and discovery? PLoS Pathog. 2011;7:e1002344.Poland G.A., Ovsyannikova I.G., Jacobson R.M. Vaccine immunogenetics: bedside to bench to population. Vaccine. 2008;26:6183-6188.Poland G.A., Ovsyannikova I.G., Jacobson R.M. Vaccine immunogenetics: bedside to bench to population. Vaccine. 2008;26:6183-6188.Pulendran B., Miller J., Querec T.D., Akondy R., Moseley N., Laur O., Glidewell J., Monson N., Zhu T., Zhu H., Staprans S., Lee D., Brinton M.A., Perelygin A.A., Vellozzi C., Brachman P. Jr., Lalor S., Teuwen D., Eidex R.B., Cetron M., Priddy F., del Rio C., Altman J., Ahmed R. Case of yellow fever vaccine – associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes. J. Infect. Dis. 2008;198:500-507. DOI 10.1086/590187.Pulendran B., Miller J., Querec T.D., Akondy R., Moseley N., Laur O., Glidewell J., Monson N., Zhu T., Zhu H., Staprans S., Lee D., Brinton M.A., Perelygin A.A., Vellozzi C., Brachman P. Jr., Lalor S., Teuwen D., Eidex R.B., Cetron M., Priddy F., del Rio C., Altman J., Ahmed R. Case of yellow fever vaccine – associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes. J. Infect. Dis. 2008;198:500-507. DOI 10.1086/590187.Sambrook J., Russell D.W. The condensed protocols from Molecular cloning: a laboratory manual. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2006.Sambrook J., Russell D.W. The condensed protocols from Molecular cloning: a laboratory manual. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2006.Sanda C., Weitzel P., Tsukahara T., Schaley J., Edenberg H.J., Stephens M.A., McClintick J.N., Blatt L.M., Li L., Brodsky L., Taylor M.W. Differential gene induction by type I and type II inter ferons and their combination. J. Interferon Cytokine Res. 2006;26:462-472.Sanda C., Weitzel P., Tsukahara T., Schaley J., Edenberg H.J., Stephens M.A., McClintick J.N., Blatt L.M., Li L., Brodsky L., Taylor M.W. Differential gene induction by type I and type II inter ferons and their combination. J. Interferon Cytokine Res. 2006;26:462-472.Thamizhmani R., Vijayachari P. Association of dengue virus infection susceptibility with polymorphisms of 2′-5′-oligoadenylatesynthetase genes: a case-control study. Braz. J. Infect. Dis. 2014;18:548550.Thamizhmani R., Vijayachari P. Association of dengue virus infection susceptibility with polymorphisms of 2′-5′-oligoadenylatesynthetase genes: a case-control study. Braz. J. Infect. Dis. 2014;18:548550.UCSC Genome Browser Gateway. 2017. Available at http://genome– euro.ucsc.edu/cgi–bin/hgGateway?hgsid=225788287_h9nI4RnxWsBd3VHZFAl6jALan0UJ.UCSC Genome Browser Gateway. 2017. Available at http://genome– euro.ucsc.edu/cgi–bin/hgGateway?hgsid=225788287_h9nI4RnxWsBd3VHZFAl6jALan0UJ.Valarcher J.F., Hägglund S., Juremalm M., Blomqvist G., Renström L., Zohari S., Leijon M., Chirico J. Tick-borne encephalitis. Rev. Sci. Tech. 2015;34:453-466.Valarcher J.F., Hägglund S., Juremalm M., Blomqvist G., Renström L., Zohari S., Leijon M., Chirico J. Tick-borne encephalitis. Rev. Sci. Tech. 2015;34:453-466.Vector-Best Company. Reagents for cytokine analysis. 2004. Available at http://www.cytokines.ru/2004/4/Art12.php. (in Russian)Vector-Best Company. Reagents for cytokine analysis. 2004. Available at http://www.cytokines.ru/2004/4/Art12.php. (in Russian)Yakub I., Lillibridge K.M., Moran A., Gonzalez O.Y., Belmont J., Gibbs R.A., Tweardy D.J. Single nucleotide polymorphisms in genes for 2′-5′-oligoadenylatesynthetase and RNase L in patients hospitalized with West Nile virus infection. J. Infect. Dis. 2005;192: 1741-1748.Yakub I., Lillibridge K.M., Moran A., Gonzalez O.Y., Belmont J., Gibbs R.A., Tweardy D.J. Single nucleotide polymorphisms in genes for 2′-5′-oligoadenylatesynthetase and RNase L in patients hospitalized with West Nile virus infection. J. Infect. Dis. 2005;192: 1741-1748.Yudin N.S., Barkhash A.V., Maksimov V.N., Ignatieva E.V., Romaschenko A.G. Human genetic predisposition to diseases caused by viruses from Flaviviridae fa mily. Molecular Biology (Moscow). 2018;52:165-181.Yudin N.S., Barkhash A.V., Maksimov V.N., Ignatieva E.V., Romaschenko A.G. Human genetic predisposition to diseases caused by viruses from Flaviviridae fa mily. Molecular Biology (Moscow). 2018;52:165-181.Zamorano J., Rivas M.D., Pérez M. Interleukin-4: A multifunctional cytokine. Inmunologia. 2003;22:215-224.Zamorano J., Rivas M.D., Pérez M. Interleukin-4: A multifunctional cytokine. Inmunologia. 2003;22:215-224.

The authors declare that there are no conflicts of interest present.