БИОХИМИЯ, 2021, том 86, вып. 3, с. 341–359

УДК 571.27

Молекулярные и клеточные механизмы патогенеза респираторно-синцитиальной вирусной инфекции. Новые данные на экспериментальных моделях

Обзор

© 2021 И.П. Шиловский *, К.В. Юмашев, А.А. Никольский, Л.И. Вишнякова, М.Р. Хаитов

Государственный научный центр «Институт иммунологии» Федерального медико-биологического агентства, 115522 Москва, Россия; электронная почта: ip.shilovsky@nrcii.ru

Поступила в редакцию 29.07.2020
После доработки 18.10.2020
Принята к публикации 18.10.2020

DOI: 10.31857/S0320972521030052

КЛЮЧЕВЫЕ СЛОВА: молекулярные механизмы, респираторно-синцитиальный вирус, патогенез, экспериментальные модели.

Аннотация

Респираторно-синцитиальный вирус (РСВ) может вызывать тяжёлые инфекции нижних дыхательных путей у младенцев, людей с ослабленным иммунитетом и пожилых людей. Несмотря на десятилетия исследований этого патогена, отсутствует одобренная для медицинского применения профилактическая вакцина, а многие терапевтические средства все ещё находятся на различных стадиях разработки. Ускорить создание средств профилактики и лечения может детальное раскрытие механизмов патогенеза РСВ-инфекции. Патогенез этого заболевания изучают с использованием клинического материала от пациентов, однако детальные представления о молекулярных и клеточных механизмах патогенеза получают, используя модели РСВ-инфекции на животных. Чаще всего в качестве модельного вида используют мышей, т.к. они позволяют воспроизвести основные проявления патологии (обструкция бронхов, гиперсекреция слизи и воспаление лёгких, опосредованное лимфоцитами, макрофагами и нейтрофилами). Кроме того, их использование экономически целесообразно, а также доступен широкий спектр молекулярно-биологического инструментария, позволяющего изучать механизмы патогенеза на клеточном и молекулярном уровнях. В данном обзоре обобщены новые данные о патогенезе РСВ-инфекции, полученные с использованием моделей на мышах. На этих моделях показана роль Т-клеток как в антивирусной защите, так и в развитии иммунопатологии лёгких. Т-клетки осуществляют элиминацию инфицированных клеток, они же продуцируют значительные количества провоспалительных цитокинов TNFα и IFNγ. Недавно была выявлена новая популяция тканерезидентных Т-клеток памяти (TRM). Они обладают выраженным антивирусным эффектом, при этом не вызывают иммунопатологии лёгких. Накопление TRM происходит после локального (а не системного) введения РСВ-антигенов. Этот факт может быть в дальнейшем использован при разработке эффективных подходов к вакцинации. Также с использованием моделей на мышах показана незначительная роль интерферонов в антивирусной защите от РСВ. Этот патоген обладает механизмами «ухода» от действия антивирусных интерферонов типа I и III, что может объяснять низкую эффективность интерферон-содержащих лекарственных препаратов по отношению к РСВ. Благодаря технологии нокаута генов у лабораторных мышей был совершён значительный прорыв в понимании роли ряда провоспалительных цитокинов в иммунопатологии лёгких. Помимо TNFα и IFNγ, было установлено, что цитокины IL-4, IL-5, IL-13, IL-17A, IL-33 и TSLP опосредуют основные проявления патологии: обструкцию бронхов, продукцию слизи, инфильтрацию лёгких провоспалительными клетками. В то же время IL-6, IL-10 и IL-27 оказывали благоприятный эффект. Несмотря на значительные отличия в иммунной системе лабораторных мышей и человека, экспериментальные модели на этих животных внесли существенный вклад в раскрытие молекулярных и клеточных механизмов патогенеза РСВ-инфекции.

Сноски

* Адресат для корреспонденции.

Финансирование

Работа выполнена при поддержке Российского научного фонда (гранат № 18-74-10002).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания выполненных авторами исследований с участием людей или использованием животных в качестве объектов.

Список литературы

1. Troeger, C., Blacker, B., Khalil, I. A., Rao, P. C., Cao, J., et al. (2018) Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016, Lancet Infect. Dis., 18, 1191-1210, doi: 10.1016/S1473-3099(18)30310-4.

2. Fauroux, B., Simões, E. A. F., Checchia, P. A., Paes, B., Figueras-Aloy, J., et al. (2017) The burden and long-term respiratory morbidity associated with respiratory syncytial virus infection in early childhood, Infect. Dis. Ther., 6, 173-197, doi: 10.1007/s40121-017-0151-4.

3. Shi, T., Denouel, A., Tietjen, A. K., Campbell, I., Moran, E., Li, X., et al. (2019) Global disease burden estimates of respiratory syncytial virus–associated acute respiratory infection in older adults in 2015: a systematic review and meta-analysis, J. Infect. Dis., 222, S577-S583, doi: 10.1093/infdis/jiz059.

4. Ebbert, J. O., and Limper, A. H. (2005) Respiratory syncytial virus pneumonitis in immunocompromised adults: clinical features and outcome, Respiration, 72, 263-269, doi: 10.1159/000085367.

5. Edwards, M. R., Walton, R. P., Jackson, D. J., Feleszko, W., Skevaki, C., et al. (2017) The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations, Allergy, 73, 50-63, doi: 10.1111/all.13257.

6. Shi, T., McAllister, D. A., O’Brien, K. L., Simoes, E. A. F., Madhi, S. A., et al. (2017) Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study, Lancet, 390, 946–958, doi: 10.1016/S0140-6736(17)30938-8.

7. Halasa, N. B., Williams, J. V., Wilson, G. J., Walsh, W. F., Schaffner, W., and Wright, P. F. (2005) Medical and economic impact of a respiratory syncytial virus outbreak in a neonatal intensive care unit, Pediatr. Infect. Dis. J., 24, 1040-1044, doi: 10.1097/01.inf.0000190027.59795.ac.

8. Muralidharan, A., Li, C., Wang, L., and Li, X. (2017) Immunopathogenesis associated with formaldehyde-inactivated RSV vaccine in preclinical and clinical studies, Expert Rev.Vaccines, 16, 351-360, doi: 10.1080/14760584.2017.1260452.

9. Wang, D., Cummins, C., Bayliss, S., Sandercock, J., and Burls, A. (2008) Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation, Health Technol. Assess., 12, 1-86, doi: 10.3310/hta12360.

10. Mazur, N. I., Higgins, D., Nunes, M. C., Melero, J. A., Langedijk, A. C., et al. (2018) The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates, Lancet Infect. Dis., 18, e295-e311, doi: 10.1016/S1473-3099(18)30292-5.

11. Khaitov, M. R., Litvin, L. S., Shilovskiy, I. P., Bashkatova, Yu. N., Fayzuloev, E. B., and Zverev, V. V. (2010) RNA interference. New approaches to develop antivirals [in Russian], Immunologiya, 31, 69-76.

12. Osminkina, L. A., Timoshenko, V. Y., Shilovsky, I. P., Kornilaeva, G. V., Shevchenko, S. N., et al. (2014) Porous silicon nanoparticles as scavengers of hazardous viruses, J. Nanoparticle Res., 16, 1-10, doi: 10.1007/s11051-014-2430-2.

13. Shilovskiy, I. P., Andreev, S. M., Kozhikhova, K. V., Nikolskii, A. A., and Khaitov, M. R. (2019) Prospects for the use of peptides against respiratory syncytial virus, Mol. Biol., 53, 484-500, doi: 10.1134/S0026893319040125.

14. Heylen, E., Neyts, J., and Jochmans, D. (2017) Drug candidates and model systems in respiratory syncytial virus antiviral drug discovery, Biochem. Pharmacol., 127, 1-12, doi: 10.1016/j.bcp.2016.09.014.

15. DeVincenzo, J., Lambkin-Williams, R., Wilkinson, T., Cehelsky, J., Nochur, S., et al. (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus, Proc. Natl. Acad. Sci. USA, 107, 8800-8805, doi: 10.1073/pnas.0912186107.

16. Taylor, G. (2017) Animal models of respiratory syncytial virus infection, Vaccine, 35, 469-480, doi: 10.1016/j.vaccine.2016.11.054.

17. Altamirano-Lagos, M. J., Díaz, F. E., Mansilla, M. A., Rivera-Pérez, D., Soto, D., et al. (2019) Current animal models for understanding the pathology caused by the respiratory syncytial virus, Front. Microbiol., 10, 873, doi: 10.3389/fmicb.2019.00873.

18. Battles, M. B., and McLellan, J. S. (2019) Respiratory syncytial virus entry and how to block it, Nat. Rev. Microbiol., 17, 233–245, doi: 10.1038/s41579-019-0149-x.

19. Bukreyev, A., Yang, L., and Collins, P. L. (2012) The secreted g protein of human respiratory syncytial virus antagonizes antibody-mediated restriction of replication involving macrophages and complement, J. Virol., 86, 10880-10884, doi: 10.1128/JVI.01162-12.

20. Feldman, S. A, Hendry, R. M., and Beeler, J. A. (1999) Identification of a linear heparin binding domain for human respiratory syncytial virus attachment glycoprotein G, J. Virol., 73, 6610-6617, doi: 10.1128/JVI.73.8.6610-6617.1999.

21. Tripp, R. A., Jones, L. P., Haynes, L. M., Zheng, H. Q., Murphy, P. M., and Anderson, L. J. (2001) CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein, Nat. Immunol., 2, 732-738, doi: 10.1038/90675.

22. Feldman, S. A., Audet, S., and Beeler, J. A. (2000) The fusion glycoprotein of human respiratory syncytial virus facilitates virus attachment and infectivity via an interaction with cellular heparan sulfate, J. Virol., 74, 6442-6447, doi: 10.1128/jvi.74.14.6442-6447.2000.

23. Behera, A. K., Matsuse, H., Kumar, M., Kong, X., Lockey, R. F., and Mohapatra, S. S. (2001) Blocking intercellular adhesion molecule-1 on human epithelial cells decreases respiratory syncytial virus infection, Biochem. Biophys. Res. Commun., 280, 188-195, doi: 10.1006/bbrc.2000.4093.

24. Currier, M. G., Lee, S., Stobart, C. C., Hotard, A. L., Villenave, R., et al. (2016) EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression, PLoS Pathog., 12, 1-22, doi: 10.1371/journal.ppat.1005622.

25. Tayyari, F., Marchant, D., Moraes, T. J., Duan, W., Mastrangelo, P., and Hegele, R. G. (2011) Identification of nucleolin as a cellular receptor for human respiratory syncytial virus, Nat. Med., 17, 1132-1135, doi: 10.1038/nm.2444.

26. Collins, P. L., Fearns, R., and Graham, B. S. (2013) Respiratory syncytial Virus: virology, reverse genetics, and pathogenesis of disease, in Challenges and Opportunities for Respiratory Syncytial Virus Vaccines. Current Topics in Microbiology and Immunology (Anderson, L., and Graham, B., eds) Vol. 372, Springer, Berlin, Heidelberg, doi: 10.1007/978-3-642-38919-1_1.

27. Ralston, S., and Hill, V. (2009) Incidence of apnea in infants hospitalized with respiratory syncytial virus bronchiolitis, J. Pediatr., 155, 728-733, doi: 10.1016/j.jpeds.2009.04.063.

28. Johnson, J. E., Gonzales, R. A., Olson, S. J., Wright, P. F., and Graham, B. S. (2007) The histopathology of fatal untreated human respiratory syncytial virus infection, Mod. Pathol., 20, 108-119, doi: 10.1038/modpathol.3800725.

29. Welliver, T. P., Garofalo, R. P., Hosakote, Y., Hintz, K. H., Avendano, L., et al. (2007) Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses, J. Infect. Dis., 195, 1126-1136, doi: 10.1086/512615.

30. Smith, P. K., Wang, S. Z., Dowling, K. D., and Forsyth, K. D. (2001) Leucocyte populations in respiratory syncytial virus-induced bronchiolitis, J. Paediatr. Child Health., 37, 146-151, doi: 10.1046/j.1440-1754.2001.00618.x.

31. Rosenberg, H. F., and Domachowske, J. B. (2012) Inflammatory responses to respiratory syncytial virus (RSV) infection and the development of immunomodulatory pharmacotherapeutics, Curr. Med. Chem., 19, 1424-1431, doi: 10.2174/092986712799828346.

32. Stoppelenburg, A. J., De Roock, S., Hennus, M. P., Bont, L., and Boes, M. (2014) Elevated Th17 response in infants undergoing respiratory viral infection, Am. J. Pathol., 184, 1274-1279, doi: 10.1016/j.ajpath.2014.01.033.

33. Mosquera, R. A., Stark, J. M., Atkins, C. L., Colasurdo, G. N., Chevalier, J., et al. (2014) Functional and immune response to respiratory syncytial virus infection in aged BALB/c mice: a search for genes determining disease severity, Exp. Lung Res., 40, 40-49, doi: 10.3109/01902148.2013.859334.

34. Stokes, K. L., Chi, M. H., Sakamoto, K., Newcomb, D. C., Currier, M. G., et al. (2011) Differential pathogenesis of respiratory syncytial virus clinical isolates in BALB/c mice, J. Virol., 85, 5782-5793, doi: 10.1128/JVI.01693-10.

35. Prince, G. A., Horswood, R. L., Berndt, J., Suffin, S. C., and Chanock, R. M. (1979) Respiratory syncytial virus infection in inbred mice, Infect. Immun., 26, 764-766, doi: 10.1128/IAI.26.2.764-766.1979.

36. Taylor, G., Stott, E. J., Hughes, M., and Collins, A. P. (1984) Respiratory syncytial virus infection in mice, Infect. Immun., 43, 649-655, doi: 10.1128/IAI.43.2.649-655.1984.

37. Graham, B. S., Perkins, M. D., Wright, P. F., and Karzon, D. T. (1988) Primary respiratory syncytial virus infection in mice, J. Med. Virol., 26, 153-162, doi: 10.1002/jmv.1890260207.

38. Rameix-Welti, M. A., Le Goffic, R., Hervé, P. L., Sourimant, J., Rémot, A., et al. (2014) Visualizing the replication of respiratory syncytial virus in cells and in living mice, Nat. Commun., 5, 5104, doi: 10.1038/ncomms6104.

39. Jafri, H. S., Chávez-Bueno, S., Mejías, A., Gómez, A. M., Ríos, A., et al. (2004) Respiratory syncytial virus induces pneumonia, cytokine response, airway obstruction, and chronic inflammatory infiltrates associated with long-term airway hyperresponsiveness in mice, J. Infect. Dis., 189, 1856-1865, doi: 10.1086/386372.

40. Bitko, V., Musiyenko, A., Shulyayeva, O., and Barik, S. (2005) Inhibition of respiratory viruses by nasally administered siRNA, Nat. Med., 11, 50-55, doi: 10.1038/nm1164.

41. Lukacs, N. W., Moore, M. L., Rudd, B. D., Berlin, A. A., Collins, R. D., et al. (2006) Differential immune responses and pulmonary pathophysiology are induced by two different strains of respiratory syncytial virus, Am. J. Pathol., 169, 977-986, doi: 10.2353/ajpath.2006.051055.

42. Moore, M. L., Chi, M. H., Luongo, C., Lukacs, N. W., Polosukhin, V. V., et al. (2009) A chimeric A2 strain of respiratory syncytial virus (RSV) with the fusion protein of RSV strain line 19 exhibits enhanced viral load, mucus, and airway dysfunction, J. Virol., 83, 4185-4194, doi: 10.1128/JVI.01853-08.

43. Shilovskiy, I. P., Nikolskii, A. A., Nikonova, A. A., Gaisina, A. R., Vishniakova, L. I., et al. (2019) Respiratory syncytial virus infection in mice inducing airway disfunction associated with lung tissue infl ammation as a model of human pathology, Immunologiya, 40, 72-83, doi: 10.24411/0206-4952-2019-15008.

44. Cannon, M. J., Stott, E. J., Taylor, G., and Askonas, B. A. (1987) Clearance of persistent respiratory syncytial virus infections in immunodeficient mice following transfer of primed T cells, Immunology, 62, 133-138.

45. Jozwik, A., Habibi, M. S., Paras, A., Zhu, J., Guvenel, A., et al. (2015) RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nat. Commun., 6, 10224, doi: 10.1038/ncomms10224.

46. Schmidt, M. E., and Varga, S. M. (2018) The CD8 T cell response to respiratory virus infections, Front. Immunol., 9, 678, doi: 10.3389/fimmu.2018.00678.

47. Schmidt, M. E., and Varga, S. M. (2018) Cytokines and CD8 T cell immunity during respiratory syncytial virus infection, Cytokine, 133, 15448, doi: 10.1016/j.cyto.2018.07.012.

48. Russell, C. D., Unger, S. A., Walton, M., and Schwarze, J. (2017) The human immune response to respiratory syncytial virus infection, Clin. Microbiol. Rev., 30, 481-502, doi: 10.1128/CMR.00090-16.

49. Morabito, K. M., Ruckwardt, T. R., Redwood, A. J., Moin, S. M., Price, D. A., and Graham, B. S. (2017) Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung, Mucosal Immunol., 10, 545-554, doi: 10.1038/mi.2016.48.

50. Cannon, M. J., Openshaw, P. J. M., and Askonas, B. A. (1988) Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus, J. Exp. Med., 168, 1163-1168, doi: 10.1084/jem.168.3.1163.

51. Graham, B. S., Bunton, L. A., Wright, P. F., and Karzon, D. T. (1991) Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice, J. Clin. Investig., 88, 1026-1033, doi: 10.1172/JCI115362.

52. Schmidt, M. E., Knudson, C. J., Hartwig, S. M., Pewe, L. L., Meyerholz, D. K., et al. (2018) Memory CD8 T cells mediate severe immunopathology following respiratory syncytial virus infection, PLoS Pathog., 14, doi: 10.1371/journal.ppat.1006810.

53. Ostler, T., Davidson, W., and Ehl, S. (2002) Virus clearance and immunopathology by CD8+ T cells during infection with respiratory syncytial virus are mediated by IFN-γ, Eur. J. Immunol., 32, 2117-2123, doi: 10.1002/1521-4141(200208)32:8<2117::AID-IMMU2117>3,0.CO;2-C.

54. Slütter, B., Pewe, L. L., Kaech, S. M., and Harty, J. T. (2013) Lung airway-surveilling CXCR3hi memory CD8+ T cells are critical for protection against influenza A virus, Immunity, 39, 939-948, doi: 10.1016/j.immuni.2013.09.013.

55. Channappanavar, R., Fett, C., Zhao, J., Meyerholz, D. K., and Perlman, S. (2014) Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection, J. Med. Virol., 88, 11034-11044, doi: 10.1128/JVI.01505-14.

56. Connors, T. J., Ravindranath, T. M., Bickham, K. L., Gordon, C. L., Zhang, F., et al. (2016) Airway CD8+ T cells are associated with lung injury during infant viral respiratory tract infection, Am. J. Respir. Cell Mol. Biol., 54, 822-830, doi: 10.1165/rcmb.2015-0297OC.

57. El Saleeby, C. M., Suzich, J., Conley, M. E., and DeVincenzo, J. P. (2004) Quantitative effects of palivizumab and donor-derived T cells on chronic respiratory syncytial virus infection, lung disease, and fusion glycoprotein amino acid sequences in a patient before and after bone marrow transplantation, Clin. Infect. Dis., 39, 17-20, doi: 10.1086/421779.

58. Fulton, R. B., Meyerholz, D. K., and Varga, S. M. (2010) Foxp3 + CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection, Eur. J. Immunol., 185, 2382-2392, doi: 10.4049/jimmunol.1000423.

59. Liu, J., Ruckwardt, T. J., Chen, M., Nicewonger, J. D., Johnson, T. R., and Graham, B. S. (2010) Epitope-specific regulatory CD4 T cells reduce virus-induced illness while preserving CD8 T-cell effector function at the site of infection, J. Virol., 84, 10501-10509, doi: 10.1128/JVI.00963-10.

60. Sun, J., Madan, R., Karp, C. L., and Braciale, T. J. (2009) Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10, Nat. Med., 15, 277-284, doi: 10.1038/nm.1929.

61. Loebbermann, J., Schnoeller, C., Thornton, H., Durant, L., Sweeney, N. P., et al. (2012) IL-10 regulates viral lung immunopathology during acute respiratory syncytial virus infection in mice, PLoS One., 7, doi: 10.1371/journal.pone.0032371.

62. Kinnear, E., Lambert, L., McDonald, J. U., Cheeseman, H. M., Caproni, L. J., and Tregoning, J. S. (2018) Airway T cells protect against RSV infection in the absence of antibody, Mucosal Immunol., 11, 249-256, doi: 10.1038/mi.2017.79.

63. Murawski, M. R., Bowen, G. N., Cerny, A. M., Anderson, L. J., Haynes, L. M., et al. (2009) Respiratory syncytial virus activates innate immunity through Toll-like receptor 2, J. Virol., 83, 1492-1500, doi: 10.1128/JVI.00671-08.

64. Morrison, P. T., Thomas, L. H., Sharland, M., and Friedland, J. S. (2007) RSV-infected airway epithelial cells cause biphasic up-regulation of CCR1 expression on human monocytes, J. Leukoc. Biol., 81, 87-95, doi: 10.1189/jlb.1006611.

65. Bagga, B., Cehelsky, J. E., Vaishnaw, A., Tomwilkinson, T., Meyers, R., et al. (2015) Effect of preexisting serum and mucosal antibody on experimental respiratory syncytial virus (RSV) challenge and infection of adults, J. Infect. Dis., 212, 1719-1725, doi: 10.1093/infdis/jiv281.

66. Habibi, M. S., Jozwik, A., Makris, S., Dunning, J., Paras, A., et al. (2015) Impaired antibody-mediated protection and defective IgA b-cell memory in experimental infection of adults with respiratory syncytial virus, Am. J. Respir. Crit. Care Med., 191, 1040-1049, doi: 10.1164/rccm.201412-2256OC.

67. Graham, B. S. (2019) Immunological goals for respiratory syncytial virus vaccine development, Immunity, 51, 429-442, doi: 10.1016/j.immuni.2019.08.007.

68. Mousa, J. J., Kose, N., Matta, P., Gilchuk, P., and Crowe, J. E. (2017) A novel prefusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein, Nat. Microbiol., 2, 16271, doi: 10.1038/nmicrobiol.2016.271.

69. Gilman, M. S. A., Castellanos, C. A., Chen, M., Ngwuta, J. O., Goodwin, E., et al. (2016) Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors, Sci. Immunol., 1, doi: 10.1126/sciimmunol.aaj1879.

70. Zhao, M., Zheng, Z. Z., Chen, M., Modjarrad, K., Zhang, W., et al. (2017) Discovery of a prefusion respiratory syncytial virus F-specific monoclonal antibody that provides greater in vivo protection than the murine precursor of palivizumab, J. Virol., 91, e00176-17, doi: 10.1128/JVI.00176-17.

71. Jones, H. G., Ritschel, T., Pascual, G., Brakenhoff, J. P. J., Keogh, E., et al. (2018) Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies, PLoS Pathog., 14, doi: 10.1371/journal.ppat.1006935.

72. Caidi, H., Miao, C., Thornburg, N. J., Tripp, R. A., Anderson, L. J., and Haynes, L. M. (2018) Anti-respiratory syncytial virus (RSV) G monoclonal antibodies reduce lung inflammation and viral lung titers when delivered therapeutically in a BALB/c mouse model, Antiviral Res., 154, 149-157, doi: 10.1016/j.antiviral.2018.04.014.

73. Lee Chung, H., and Jang, Y. Y. (2016) High serum ige level in the children with acute respiratory syncytial virus infection is associated with severe disease, Clin. Microbiol. Rev., 30, 481-502, doi: 10.1128/CMR.00090-16.

74. McNab, F., Mayer-Barber, K., Sher, A., Wack, A., and O’Garra, A. (2015) Type I interferons in infectious disease, Nat. Rev. Immunol., 15, 87-103, doi: 10.1038/nri3787.

75. Khaitov, M. R., Shilovskiy, I. P., and Khaitov, R. M. (2010) Type III interferons [in Russian], Usp. Sovr. Biol., 130, 147-153.

76. Kurt-Jones, E. A., Popova, L., Kwinn, L., Haynes, L. M., Jones, L. P., et al. (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus, Nat. Immunol., 1, 398-401, doi: 10.1038/80833.

77. Zeng, R., Cui, Y., Hai, Y., and Liu, Y. (2012) Pattern recognition receptors for respiratory syncytial virus infection and design of vaccines, Virus Res., 167, 138-145, doi: 10.1016/j.virusres.2012.06.003.

78. Rudd, B. D., Burstein, E., Duckett, C. S., Li, X., and Lukacs, N. W. (2005) Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression, J. Med. Virol., 79, 3350-3357, doi: 10.1128/JVI.79.6.3350-3357.2005.

79. Lukacs, N. W., Smit, J. J., Mukherjee, S., Morris, S. B., Nunez, G., and Lindell, D. M. (2010) Respiratory virus-induced TLR7 activation controls IL-17–associated increased mucus via IL-23 regulation, Eur. J. Immunol., 185, 2231-2239, doi: 10.4049/jimmunol.1000733.

80. Bhoj, V. G., Sun, Q., Bhoj, E. J., Somers, C., Chen, X., et al. (2008) MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus, Proc. Natl. Acad. Sci. USA, 105, 14046-14051, doi: 10.1073/pnas.0804717105.

81. Hashimoto, K., Durbin, J. E., Zhou, W., Collins, R. D., Ho, S. B., et al. (2005) Respiratory syncytial virus infection in the absence of STAT1 results in airway dysfunction, airway mucus, and augmented IL-17 levels, J. Allergy Clin. Immunol., 116, 550-557, doi: 10.1016/j.jaci.2005.03.051.

82. Selvaggi, C., Pierangeli, A., Fabiani, M., Spano, L., Nicolai, A., et al. (2014) Interferon lambda 1-3 expression in infants hospitalized for RSV or HRV associated bronchiolitis, J. Infect., 68, 467-477, doi: 10.1016/j.jinf.2013.12.010.

83. Sun, Y., Jain, D., Koziol-White, C. J., Genoyer, E., Gilbert, M., et al. (2015) Immunostimulatory defective viral genomes from respiratory syncytial virus promote a strong innate antiviral response during infection in mice and humans, PLoS Pathog., 11, doi: 10.1371/journal.ppat.1005122.

84. Cormier, S. A., Shrestha, B., Saravia, J., Lee, G. I., Shen, L., et al. (2014) Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection, J. Med. Virol., 88, 9350-9360, doi: 10.1128/JVI.00818-14.

85. Hijano, D. R., Siefker, D. T., Shrestha, B., Jaligama, S., Vu, L. D., et al. (2018) Type I interferon potentiates IgA immunity to respiratory syncytial virus infection during infancy, Sci. Rep., 8, 11034, doi: 10.1038/s41598-018-29456-w.

86. Goritzka, M., Makris, S., Kausar, F., Durant, L. R., Pereira, C., et al. (2015) Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes, J. Exp. Med., 212, 699-714, doi: 10.1084/jem.20140825.

87. Scotta, M. C., Machado, D. G., Oliveira, S. G., de Moura, A., Estorgato, G. R., et al. (2019) Evaluation of nasal levels of interferon and clinical severity of influenza in children, J. Clin. Virol., 114, 37-42, doi: 10.1016/j.jcv.2019.02.003.

88. Yu, C. F., Peng, W.-M., Schlee, M., Barchet, W., Eis-Hübinger, A. M., et al. (2018) SOCS1 and SOCS3 target IRF7 degradation to suppress TLR7-mediated type I IFN production of human plasmacytoid dendritic cells, Eur. J. Immunol., 200, 4024-4035, doi: 10.4049/jimmunol.1700510.

89. Christiaansen, A. F., Syed, M. A., Ten Eyck, P. P., Hartwig, S. M., Durairaj, L., et al. (2016) Altered Treg and cytokine responses in RSV-infected infants, Pediatr. Res., 80, 702-709, doi: 10.1038/pr.2016.130.

90. Thwaites, R. S., Coates, M., Ito, K., Ghazaly, M., Feather, C., et al. (2018) Reduced nasal viral load and IFN responses in infants with respiratory syncytial virus bronchiolitis and respiratory failure, Am. J. Respir. Crit. Care Med., 198, 1074-1084, doi: 10.1164/rccm.201712-2567OC.

91. Eichinger, K. M., and Empey, K. M. (2017) Data describing IFNγ-mediated viral clearance in an adult mouse model of respiratory syncytial virus (RSV), Data Brief, 14, 272-277, doi: 10.1016/j.dib.2017.07.034.

92. Lee, Y. M., Miyahara, N., Takeda, K., Prpich, J., Oh, A., et al. (2008) IFN-γ production during initial infection determines the outcome of reinfection with respiratory syncytial virus, Am. J. Respir. Crit. Care Med., 177, 208-218, doi: 10.1164/rccm.200612-1890OC.

93. Mejias, A., Dimo, B., Suarez, N. M., Garcia, C., Suarez-Arrabal, M. C., et al. (2013) Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection, PLoS Med., 10, doi: 10.1371/journal.pmed.1001549.

94. Tang, Y. W., and Graham, B. S. (1994) Anti-IL-4 treatment at immunization modulates cytokine expression, reduces illness, and increases cytotoxic T lymphocyte activity in mice challenged with respiratory syncytial virus, J. Clin. Invest., 94, 1953-1958, doi: 10.1172/JCI117546.

95. Vu, L. D., Siefker, D., Jones, T. L., You, D., Taylor, R., et al. (2019) Elevated levels of type 2 respiratory innate lymphoid cells in human infants with severe respiratory syncytial virus bronchiolitis, Am. J. Respir. Crit. Care Med., 200, 1414-1423, doi: 10.1164/rccm.201812-2366OC.

96. Bukreyev, A., Belyakov, I. M., Prince, G. A., Yim, K. C., Harris, K. K., et al. (2005) Expression of interleukin-4 by recombinant respiratory syncytial virus is associated with accelerated inflammation and a nonfunctional cytotoxic T-lymphocyte response following primary infection but not following challenge with wild-type virus, J. Virol., 79, 9515-9526, doi: 10.1128/JVI.79.15.9515-9526.2005.

97. Stier, M. T., Bloodworth, M. H., Toki, S., Newcomb, D. C., Goleniewska, K., et al. (2016) Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin, J. Allergy Clin. Immunol., 138, 814-824, doi: 10.1016/j.jaci.2016.01.050.

98. Mukherjee, S., Lindell, D. M., Berlin, A. A., Morris, S. B., Shanley, T. P., et al. (2011) IL-17Induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease, Am. J. Pathol., 179, 248-258, doi: 10.1016/j.ajpath.2011.03.003.

99. Pyle, C. J., Uwadiae, F. I., Swieboda, D. P., and Harker, J. A. (2017) Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology, PLoS Pathog., 13, doi: 10.1371/journal.ppat.1006640.

100. Antwi-Amoabeng, D., Kanji, Z., Ford, B., Beutler, B. D., Riddle, M. S., and Siddiqui, F. (2020) Clinical outcomes in COVID-19 patients treated with tocilizumab: an individual patient data systematic review, J. Med. Virol., doi: 10.1002/jmv.26038.

101. Lan, S. H., Lai, C. C., Huang, H. T., Chang, S. P., Lu, L. C., and Hsueh, P. R. (2020) Tocilizumab for severe COVID-19: a systematic review and meta-analysis, Int. J. Antimicrob. Agents, 56, 106103, doi: 10.1016/j.ijantimicag.2020.106103.

102. Pacha, O., Sallman, M. A., and Evans, S. E. (2020) COVID-19: a case for inhibiting IL-17? Nat. Rev. Immunol., 20, 345-346, doi: 10.1038/s41577-020-0328-z.

103. Shilovskiy, I., Nikolskii, A., Kurbacheva, O., and Khaitov, M. (2020) Modern view of neutrophilic asthma molecular mechanisms and therapy, Biochemistry (Moscow), 85, 854-868, doi: 10.1134/S0006297920080027.

104. Saravia, J., You, D., Shrestha, B., Jaligama, S., Siefker, D., et al. (2015) Respiratory syncytial virus disease is mediated by age-variable IL-33, PLoS Pathog., 11, doi: 10.1371/journal.ppat.1005217.

105. Krasnikh, L. M., Gaisina, A. R., Shilovskiy, I. P., Nikonova, A. A., Mitin, A. N., et al. (2018) The study of pharmacological efficiency of sirna tarfeted to il-33 on the mouse model of virus-induced exacerbations of bronchial asthma, Russ. J. Biopharm., 10, 49-55.

106. Liu, T., Castro, S., Brasier, A. R., Jamaluddin, M., Garofalo, R. P., and Casola, A. (2004) Reactive oxygen species mediate virus-induced STAT activation: role of tyrosine phosphatases, J. Biol. Chem., 279, 2461-2469, doi: 10.1074/jbc.M307251200.

107. Ren, K., Lv, Y., Zhuo, Y., Chen, C., Shi, H., et al. (2016) Suppression of IRG-1 reduces inflammatory cell infiltration and lung injury in respiratory syncytial virus infection by reducing production of reactive oxygen species, J. Virol., 90, 7313-7322, doi: 10.1128/JVI.00563-16.