Вопросы вирусологии. 2022; 67: 142-152
Биологическая активность интерферонов при новой коронавирусной инфекции COVID-19
https://doi.org/10.36233/0507-4088-99Аннотация
Введение. Иммунопатогенез новой коронавирусной инфекции COVID-19 принято связывать с развитием дисбаланса в иммунном ответе на её возбудитель – вирус SARS-CoV-2 (Coronaviridae: Coronavirinae: Betacoronavirus: Sarbecovirus). Это проявляется, в частности, дефицитом интерферонов (IFN) в начале заболевания с последующей гиперпродукцией провоспалительных цитокинов. Вирус вызывает снижение количества IFN I (α/β) и III типов (λ); менее изучены изменения, касающиеся IFN II типа (γ). В этой связи актуальным является определение функционального биологически активного IFN (интерферонового статуса) при COVID-19.
Цель исследования – оценка противовирусного потенциала организма посредством определения биологически активных IFN при новой коронавирусной инфекции.
Материал и методы. В работе использованы биологические образцы сыворотки крови пациентов с COVID-19, взятые в острую фазу (110 пациентов в 1–5 сутки болезни) и во время реабилитации (47 человек в период 1–3 мес. c момента начала заболевания). Оценка интерферонового статуса осуществлялась в соответствии с методикой, разработанной авторами и описанной ранее.
Результаты. В ходе эксперимента изучен IFN-статус пациентов с COVID-19 в остром периоде и в фазе постинфекционной реабилитации. Установлено, что SARS-CoV-2 вызывает выраженное угнетение биологической активности IFN I и II типов по сравнению с референтными значениями – более чем в 20 и 7 раз соответственно. На протяжении постковидного периода зарегистрировано неполное восстановление активности системы IFN, протекавшее весьма медленно. За время наблюдения не выявлено ни одного случая достижения физиологических показателей интерферонового статуса.
Заключение. Полученные данные по выявлению дефицита функционального биологически активного IFN подтверждают гипотезу о превалирующей роли нарушения процессов выработки IFN различных типов в иммунопатогенезе COVID-19.
Список литературы
1. Постановление Правительства РФ № 66 «О внесении изменения в перечень заболеваний, представляющих опасность для окружающих». М.; 2020.
2. Park A., Iwasaki A. Type I and type III interferons – induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe. 2020; 27(6): 870–8. https://doi.org/10.1016/j.chom.2020.05.008
3. COVID-19 Data Repository by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. Availible at: https://github.com/CSSEGISandData/COVID-19 (accessed 2 April 2022)
4. Coronavirus (COVID-19) confirmed cases, new cases, recoveries, and deaths in Russia as of March 23, 2022, by federal subject. Availible at: https://www.statista.com/statistics/1102935/coronavirus-casesby-region-in-russia/ (accessed 2 April 2022).
5. Lei X., Dong X., Ma R., Wang W., Xiao X., Tian Z., et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat. Commun. 2020; 11(1): 3810. https://doi.org/10.1038/s41467-020-17665-9
6. Galani I.E., Rovina N., Lampropoulou V., Triantafyllia V., Manioudaki M., Pavlos E., et al. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat. Immunol. 2021; 22(1): 32–40. https://doi.org/10.1038/s41590-020-00840-x
7. Felgenhauer U., Schoen A., Gad H.H., Hartmann R., Schaubmar A.R., Failing K., et al. Inhibition of SARS-CoV-2 by type I and type III interferons. J. Biol. Chem. 2020; 295(41): 13958–64. https://doi.org/10.1074/jbc.AC120.013788
8. Busnadiego I., Fernbach S., Pohl M.O., Karakus U., Huber M., Trkola A., et al. Antiviral activity of type I, II, and III interferons counterbalances ACE2 inducibility and restricts SARS-CoV-2. mBio. 2020; 11(5): e01928-20. https://doi.org/10.1128/mBio.01928-20
9. Wei L., Ming S., Zou B., Wu Y., Hong Z., Li Z., et al. Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes During Covid-19 Infection. SSRN Journal. 2020. https://dx.doi.org/10.2139/ssrn.3564998 Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3564998 (accessed December 16, 2021).
10. Мясников А.Л., Бернс С.А., Талызин П.А., Ершов Ф.И. Интерферон гамма в терапии пациентов с COVID-19 среднетяжелого течения. Вопросы вирусологии. 2021; 66(1) 47–54. https://doi.org/10.36233/0507-4088-24
11. Ершов Ф.И., Оспельникова Т.П., Наровлянский А.Н. Интерфероновый статус как метод определения неспецифических биомаркеров иммунопатологии человека. Журнал микробиологии, эпидемиологии и иммунобиологии. 2019; (3): 91–9. https://doi.org/10.36233/0372-9311-2019-3-91-99
12. Оспельникова Т.П., Морозова О.В., Андреева С.А., Исаева Е.И., Koлoдяжная Л.В., Колобухина Л.В., и др. Отличия спектров РНК интерферонов и интерферон-индуцируемого гена MX1 при гриппозной и аденовирусной инфекциях. Иммунология. 2018; 39(5-6): 290–3. http://dx.doi.org/10.18821/0206-4952-2018-39-5-6-290-293
13. Оспельникова Т.П., Колодяжная Л.В., Табаков В.Ю., Ершов Ф.И. Способ определения продукции интерферонов как параметров врожденного иммунитета. Патент РФ №2657808; 2018. https://i.moscow/patents/RU2657808C1_20180615 (accessed December 16, 2021).
14. Cai Y., Zhang J., Xiao T., Peng H., Sterling S.M., Walsh R.M. Jr., et al. Distinct conformational states of SARS-CoV-2 spike protein. Science. 2020; 369(6511): 1586–92. https://doi.org/10.1126/science.abd4251
15. Thoms M., Buschauer R., Ameismeier M., Koepke L., Denk T., Hirschenberger M., et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020; 369(6508): 1249–55. https://doi.org/10.1126/science.abc8665
16. Ou X., Liu Y., Lei X., Li P., Mi D., Ren L., et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 2020; 11(1): 1620. https://doi.org/10.1038/s41467-020-15562-9
17. Bullerdiek J. COVID-19 challenging cell biology. Protoplasma. 2020; 257(3): 619–20. https://doi.org/10.1007/s00709-020-01506-z
18. Thevarajan I., Nguyen T.H.O., Koutsakos M., Druce J., Caly L., van de Sandt C.E., et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 2020; 26(4): 453–5. https://doi.org/10.1038/s41591-020-0819-2
19. Министерство здравоохранения Российской Федерации. Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)». Версия 11 (07.05.2021). Available at: https://minzdrav.gov.ru/ministry/med_covid19
20. Lapić I., Rogić D., Plebani M. Erythrocyte sedimentation rate is associated with severe coronavirus disease 2019 (COVID-19): a pooled analysis. Clin. Chem. Lab. Med. 2020; 58(7): 1146–8. https://doi.org/10.1515/cclm-2020-0620
21. Vabret N., Britton G.J., Gruber C., Hegde S., Kim J., Kuksin M., et al. Immunology of COVID-19: current state of the science. Immunity. 2020; 52(6): 910–41. https://doi.org/10.1016/j.immuni.2020.05.002
22. Симбирцев А.С. Иммунопатогенез и перспективы иммунотерапии коронавирусной инфекции. ВИЧ-инфекция и иммуносупрессия. 2020; 12(4): 7–22. https://doi.org/10.22328/2077-9828-2020-12-4-7-22
23. Ершов Ф.И. Хронология пандемии COVID-19. М.: ГЭОТАР-Медиа; 2021.
24. Adamczyk B., Morawiec N., Arendarczyk M., Baran M., Wierzbicki K., Sowa P., et al. Multiple sclerosis immunomodulatory therapies tested for effectiveness in COVID-19. Neurol. Neurochir. Pol. 2021; 55(4): 357–68. https://doi.org/10.5603/PJNNS.a2021.0051
25. Ivashkiv L., Donlin L. Regulation of type I interferon responses. Nat. Rev. Immunol. 2014; 14(1): 36–49. https://doi.org/10.1038/nri3581
26. Ye L., Schnepf D., Staeheli P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat. Rev. Immunol. 2019; 19(10): 614–25. https://doi.org/10.1038/s41577-019-0182-z
27. Оспельникова Т.П., Исаева Е.И., Колодяжная Л.В., Козулина И.С., Андреева С.А., Полосков В.В., и др. Противовирусная активность препаратов интерферона бета-1а. Вопросы вирусологии. 2015; 60(6): 24–8.
28. Zhou Q., Chen V., Shannon C.P., Wei X.S., Xiang X., Wang X., et al. Interferon-α2b Treatment for COVID-19. Front. Immunol. 2020; 11: 1061. https://doi.org/10.3389/fimmu.2020.01061
29. Pinto D., Park Y.J., Beltramello M., Walls A.C., Tortorici M.A., Bianchi S., et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020; 583(7815): 290–5. https://doi.org/10.1038/s41586-020-2349-y
30. Neufeldt C.J., Cerikan B., Cortese M., Frankish J., Lee J.Y., Plociennikowska A., et al. SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB. Commun. Biol. 2022; 5(1): 45. https://doi.org/10.1038/s42003-021-02983-5
31. Lee J.S., Park S., Jeong H.W., Ahn J.Y., Choi S.J., Lee H., et al. Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Sci. Immunol. 2020; 5(49): eabd1554. https://doi.org/10.1126/sciimmunol.abd1554
32. Stertz S., Reichelt M., Spiegel M., Kuri T., Martínez-Sobrido L., García-Sastre A., et al. The intracellular sites of early replication and budding of SARS-coronavirus. Virology. 2007; 361(2): 304–15. https://doi.org/10.1016/j.virol.2006.11.027
33. Chen Y., Cai H., Pan J., Xiang N., Tien P., Ahola T., et al. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc. Natl. Acad. Sci. USA. 2009; 106: 3484–9. https://doi.org/10.1073/pnas.0808790106
34. Menachery V.D., Yount B.L. Jr., Josset L., Gralinski L.E., Scobey T., Agnihothram S., et al. Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 20-o-methyltransferase activity. J. Virol. 2014; 88(8): 4251–64. https://doi.org/10.1128/JVI.03571-13
35. Lokugamage K.G., Hage A., Schindewolf C., Rajsbaum R., Menachery V.D. SARS-CoV-2 is sensitive to type I interferon pretreatment. bioRxiv. 2020. Preprint. https://doi.org/10.1101/2020.03.07.982264
Problems of Virology. 2022; 67: 142-152
Biological activity of interferons in the novel coronavirus infection COVID-19
https://doi.org/10.36233/0507-4088-99Abstract
Introduction. The immunopathogenesis of the novel coronavirus infection COVID-19 is usually associated with the development of imbalance in the immune response to its causative agent, SARS-CoV-2 virus (Coronaviridae: Coronavirinae: Betacoronavirus: Sarbecovirus). This is manifested, in particular, by interferons’ (IFNs) deficiency at the beginning of the disease followed by hyperproduction of pro-inflammatory cytokines. The virus causes a decrease in IFN types I (α/β) and III (λ) levels; changes in IFN type II (γ) are less studied. In this regard, it is relevant to assess the functional bioactive IFN (interferon status) in COVID-19. The aim of the study was to assess the antiviral potential of the body by testing the biologically active IFNs in COVID-19.
Material and methods. We used biological serum samples of COVID-19 patients taken in the acute phase (110 patients on the 1–5 days of the disease) and during rehabilitation (47 patients during 1–3 months after the disease onset). Assessment of interferon status was performed according to the technique developed by the authors and described earlier.
Results. The IFN status of patients with COVID-19 in the acute period and in the phase of post-infection rehabilitation was studied during the observation period. It was found that SARS-CoV-2 causes a pronounced inhibition of biological activity of IFN types I and II compared to the reference values by more than 20 and 7 times, respectively. During the post-COVID period, incomplete recovery of the IFN system activity was registered, which proceeded very slowly. No cases of reaching physiological indicators of interferon status were identified during the observation period.
Conclusion. The obtained data on deficiency of the functional biologically active IFN confirm the hypothesis about the predominant role of impaired IFN production of different types in the immunopathogenesis of the novel coronavirus infection.
References
1. Postanovlenie Pravitel'stva RF № 66 «O vnesenii izmeneniya v perechen' zabolevanii, predstavlyayushchikh opasnost' dlya okruzhayushchikh». M.; 2020.
2. Park A., Iwasaki A. Type I and type III interferons – induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe. 2020; 27(6): 870–8. https://doi.org/10.1016/j.chom.2020.05.008
3. COVID-19 Data Repository by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. Availible at: https://github.com/CSSEGISandData/COVID-19 (accessed 2 April 2022)
4. Coronavirus (COVID-19) confirmed cases, new cases, recoveries, and deaths in Russia as of March 23, 2022, by federal subject. Availible at: https://www.statista.com/statistics/1102935/coronavirus-casesby-region-in-russia/ (accessed 2 April 2022).
5. Lei X., Dong X., Ma R., Wang W., Xiao X., Tian Z., et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat. Commun. 2020; 11(1): 3810. https://doi.org/10.1038/s41467-020-17665-9
6. Galani I.E., Rovina N., Lampropoulou V., Triantafyllia V., Manioudaki M., Pavlos E., et al. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat. Immunol. 2021; 22(1): 32–40. https://doi.org/10.1038/s41590-020-00840-x
7. Felgenhauer U., Schoen A., Gad H.H., Hartmann R., Schaubmar A.R., Failing K., et al. Inhibition of SARS-CoV-2 by type I and type III interferons. J. Biol. Chem. 2020; 295(41): 13958–64. https://doi.org/10.1074/jbc.AC120.013788
8. Busnadiego I., Fernbach S., Pohl M.O., Karakus U., Huber M., Trkola A., et al. Antiviral activity of type I, II, and III interferons counterbalances ACE2 inducibility and restricts SARS-CoV-2. mBio. 2020; 11(5): e01928-20. https://doi.org/10.1128/mBio.01928-20
9. Wei L., Ming S., Zou B., Wu Y., Hong Z., Li Z., et al. Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes During Covid-19 Infection. SSRN Journal. 2020. https://dx.doi.org/10.2139/ssrn.3564998 Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3564998 (accessed December 16, 2021).
10. Myasnikov A.L., Berns S.A., Talyzin P.A., Ershov F.I. Interferon gamma v terapii patsientov s COVID-19 srednetyazhelogo techeniya. Voprosy virusologii. 2021; 66(1) 47–54. https://doi.org/10.36233/0507-4088-24
11. Ershov F.I., Ospel'nikova T.P., Narovlyanskii A.N. Interferonovyi status kak metod opredeleniya nespetsificheskikh biomarkerov immunopatologii cheloveka. Zhurnal mikrobiologii, epidemiologii i immunobiologii. 2019; (3): 91–9. https://doi.org/10.36233/0372-9311-2019-3-91-99
12. Ospel'nikova T.P., Morozova O.V., Andreeva S.A., Isaeva E.I., Kolodyazhnaya L.V., Kolobukhina L.V., i dr. Otlichiya spektrov RNK interferonov i interferon-indutsiruemogo gena MX1 pri grippoznoi i adenovirusnoi infektsiyakh. Immunologiya. 2018; 39(5-6): 290–3. http://dx.doi.org/10.18821/0206-4952-2018-39-5-6-290-293
13. Ospel'nikova T.P., Kolodyazhnaya L.V., Tabakov V.Yu., Ershov F.I. Sposob opredeleniya produktsii interferonov kak parametrov vrozhdennogo immuniteta. Patent RF №2657808; 2018. https://i.moscow/patents/RU2657808C1_20180615 (accessed December 16, 2021).
14. Cai Y., Zhang J., Xiao T., Peng H., Sterling S.M., Walsh R.M. Jr., et al. Distinct conformational states of SARS-CoV-2 spike protein. Science. 2020; 369(6511): 1586–92. https://doi.org/10.1126/science.abd4251
15. Thoms M., Buschauer R., Ameismeier M., Koepke L., Denk T., Hirschenberger M., et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020; 369(6508): 1249–55. https://doi.org/10.1126/science.abc8665
16. Ou X., Liu Y., Lei X., Li P., Mi D., Ren L., et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 2020; 11(1): 1620. https://doi.org/10.1038/s41467-020-15562-9
17. Bullerdiek J. COVID-19 challenging cell biology. Protoplasma. 2020; 257(3): 619–20. https://doi.org/10.1007/s00709-020-01506-z
18. Thevarajan I., Nguyen T.H.O., Koutsakos M., Druce J., Caly L., van de Sandt C.E., et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 2020; 26(4): 453–5. https://doi.org/10.1038/s41591-020-0819-2
19. Ministerstvo zdravookhraneniya Rossiiskoi Federatsii. Vremennye metodicheskie rekomendatsii «Profilaktika, diagnostika i lechenie novoi koronavirusnoi infektsii (COVID-19)». Versiya 11 (07.05.2021). Available at: https://minzdrav.gov.ru/ministry/med_covid19
20. Lapić I., Rogić D., Plebani M. Erythrocyte sedimentation rate is associated with severe coronavirus disease 2019 (COVID-19): a pooled analysis. Clin. Chem. Lab. Med. 2020; 58(7): 1146–8. https://doi.org/10.1515/cclm-2020-0620
21. Vabret N., Britton G.J., Gruber C., Hegde S., Kim J., Kuksin M., et al. Immunology of COVID-19: current state of the science. Immunity. 2020; 52(6): 910–41. https://doi.org/10.1016/j.immuni.2020.05.002
22. Simbirtsev A.S. Immunopatogenez i perspektivy immunoterapii koronavirusnoi infektsii. VICh-infektsiya i immunosupressiya. 2020; 12(4): 7–22. https://doi.org/10.22328/2077-9828-2020-12-4-7-22
23. Ershov F.I. Khronologiya pandemii COVID-19. M.: GEOTAR-Media; 2021.
24. Adamczyk B., Morawiec N., Arendarczyk M., Baran M., Wierzbicki K., Sowa P., et al. Multiple sclerosis immunomodulatory therapies tested for effectiveness in COVID-19. Neurol. Neurochir. Pol. 2021; 55(4): 357–68. https://doi.org/10.5603/PJNNS.a2021.0051
25. Ivashkiv L., Donlin L. Regulation of type I interferon responses. Nat. Rev. Immunol. 2014; 14(1): 36–49. https://doi.org/10.1038/nri3581
26. Ye L., Schnepf D., Staeheli P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat. Rev. Immunol. 2019; 19(10): 614–25. https://doi.org/10.1038/s41577-019-0182-z
27. Ospel'nikova T.P., Isaeva E.I., Kolodyazhnaya L.V., Kozulina I.S., Andreeva S.A., Poloskov V.V., i dr. Protivovirusnaya aktivnost' preparatov interferona beta-1a. Voprosy virusologii. 2015; 60(6): 24–8.
28. Zhou Q., Chen V., Shannon C.P., Wei X.S., Xiang X., Wang X., et al. Interferon-α2b Treatment for COVID-19. Front. Immunol. 2020; 11: 1061. https://doi.org/10.3389/fimmu.2020.01061
29. Pinto D., Park Y.J., Beltramello M., Walls A.C., Tortorici M.A., Bianchi S., et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020; 583(7815): 290–5. https://doi.org/10.1038/s41586-020-2349-y
30. Neufeldt C.J., Cerikan B., Cortese M., Frankish J., Lee J.Y., Plociennikowska A., et al. SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB. Commun. Biol. 2022; 5(1): 45. https://doi.org/10.1038/s42003-021-02983-5
31. Lee J.S., Park S., Jeong H.W., Ahn J.Y., Choi S.J., Lee H., et al. Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Sci. Immunol. 2020; 5(49): eabd1554. https://doi.org/10.1126/sciimmunol.abd1554
32. Stertz S., Reichelt M., Spiegel M., Kuri T., Martínez-Sobrido L., García-Sastre A., et al. The intracellular sites of early replication and budding of SARS-coronavirus. Virology. 2007; 361(2): 304–15. https://doi.org/10.1016/j.virol.2006.11.027
33. Chen Y., Cai H., Pan J., Xiang N., Tien P., Ahola T., et al. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc. Natl. Acad. Sci. USA. 2009; 106: 3484–9. https://doi.org/10.1073/pnas.0808790106
34. Menachery V.D., Yount B.L. Jr., Josset L., Gralinski L.E., Scobey T., Agnihothram S., et al. Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 20-o-methyltransferase activity. J. Virol. 2014; 88(8): 4251–64. https://doi.org/10.1128/JVI.03571-13
35. Lokugamage K.G., Hage A., Schindewolf C., Rajsbaum R., Menachery V.D. SARS-CoV-2 is sensitive to type I interferon pretreatment. bioRxiv. 2020. Preprint. https://doi.org/10.1101/2020.03.07.982264
