cfpdБюллетень физиологии и патологии дыханияBulletin Physiology and Pathology of Respiration1998-5029Дальневосточный научный центр физиологии и патологии дыхания10.36604/1998-5029-2021-82-107-115cfpd-988Research ArticleОБЗОРЫREVIEWSРоль Toll-подобных рецепторов в патогенезе COVID-19Role of Toll-like receptors in COVID-19 pathogenesisСинякинИ. А.SinyakinI. А.

Иван Алексеевич Синякин, студент 3 курса лечебного факультета

675000, г. Благовещенск, ул. Горького, 95

Ivan A. Sinyakin, 3rd year Student of Medical Faculty

95 Gor'kogo Str., Blagoveshchensk, 675000

sinakinivan8@gmail.comАндриевскаяИ. А.AndrievskayaI. A.

Ирина Анатольевна Андриевская, д-р биол. наук, профессор РАН, зав. лабораторией механизмов этиопатогенеза и восстановительных процессов дыхательной системы при неспецифических заболеваниях легких

675000, г. Благовещенск, ул. Калинина, 22

Irina A. Andrievskaya, PhD, DSc (Biol.), Professor of RAS, Head of Laboratory of Mechanisms of Etiopathogenesis and Recovery Processes of the Respiratory System at Non-Specific Lung Diseases

22 Kalinina Str., Blagoveshchensk, 675000

irina-andrievskaja@rambler.ruИшутинаН. А.IshutinaN. A.

Наталия Александровна Ишутина, д-р биол. наук, ведущий научный сотрудник, лаборатория механизмов этиопатогенеза и восстановительных процессов дыхательной системы при неспецифических заболеваниях легких

675000, г. Благовещенск, ул. Калинина, 22

Nataliа A. Ishutina, PhD, DSc (Biol.), Leading Staff Scientist, Laboratory of Mechanisms of Etiopathogenesis and Recovery Processes of the Respiratory System at Non-Specific Lung Diseases

22 Kalinina Str., Blagoveshchensk, 675000

ishutina-na@mail.ruБаталоваТ. А.BatalovaT. A.

Татьяна Анатольевна Баталова, д-р биол. наук, доцент, зав. кафедрой физиологии и патофизиологии

675000, г. Благовещенск, ул. Горького, 95

Tatiana A. Batalova, PhD, DSc (Biol.), Associate Professor, Head of Department of Physiology and Pathophysiology

95 Gor'kogo Str., Blagoveshchensk, 675000

batalova_ta@mail.ruГригорьевН. Р.Grigor'evN. R.

Николай Романович Григорьев, д-р мед. наук, профессор, профессор кафедры физиологии и патофизиологии

675000, г. Благовещенск, ул. Горького, 95

Nikolay R. Grigor'ev, PhD, DSc (Med.), Professor, Professor of Department of Physiology and Pathophysiology

95 Gor'kogo Str., Blagoveshchensk, 675000

nikagrig@yandex.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Амурская государственная медицинская академия» Министерства здравоохранения Российской ФедерацииAmur State Medical AcademyФедеральное государственное бюджетное научное учреждение «Дальневосточный научный центр физиологии и патологии дыхания»Far Eastern Scientific Center of Physiology and Pathology of Respiration202123122021082107115Copyright © Синякин И.А., Андриевская И.А., Ишутина Н.А., Баталова Т.А., Григорьев Н.Р., 20212021Синякин И.А., Андриевская И.А., Ишутина Н.А., Баталова Т.А., Григорьев Н.Р.Sinyakin I.А., Andrievskaya I.A., Ishutina N.A., Batalova T.A., Grigor'ev N.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cfpd.elpub.ru/jour/article/view/988

Введение. В данном обзоре обобщена имеющаяся информация о роли Toll-подобных рецепторов (TLRs) в патогенезе новой коронавирусной инфекции COVID‐19, вызванной SARS‐CoV‐2. Точный патогенез COVID‐19 и роль каждого компонента врожденного и адаптивного иммунитета до сих пор не известны. Цель. Обсуждение возможной роли TLRs в иммунном ответе при COVID‐19 инфекции. Результаты. Анализ литературы в базе данных PubMed показал, что в механизме проникновения SARS-CoV-2 и лизисе альвеолоцитов II типа лежит связывание спайкового S-гликопротеина или капсидного белка М вируса с рецептор-связывающим доменом ACE2 на поверхности эпителиальных клеток. Миграция и инфильтрация воспалительных клеток приводит к сверхактивации TLR4 на поверхности альвеолоцитов и бронхиального эпителия, смещая процесс к MyD88-зависимой острой воспалительной сигнализации и гиперсекреции провоспалительных цитокинов, вызывающих «цитокиновый шторм» и развитие тяжелых осложнений COVID‐19 инфекции, в частности, острого респираторного диcтресс-синдрома, дыхательной недостаточности, патологии внутренних органов, а, в некоторых случаях, смерти пациента. Заключение. Возможно, предположить, что TLRs оказывают воздействие на иммунный ответ при инфекции COVID‐19. Как антагонисты, так и агонисты TLRs, в зависимости от их типа, могут быть исследованы для определения терапевтического и негативного воздействия при COVID‐19 инфекции. Следует проводить дальнейшее исследование по изучению TLRs и путей активации цитокиновой экспрессии, поскольку они указывают на прямую связь со смертностью и восприимчивостью к вирусу. Биоинформатические исследования также могут помочь лучше понять взаимодействие TLRs с белками и РНК возбудителя SARS‐CoV‐2

Introduction. This review summarizes the available information on the role of Toll-like receptors (TLRs) in the pathogenesis of the novel coronavirus infection COVID-19 induced by SARS-CoV-2. The exact pathogenesis of COVID-19 and the role of each component of innate and adaptive immunity are still unknown. Aim. Discussion of the possible role of TLRs in the immune response in COVID-19 infection. Results. Analysis of the literature in the PubMed database showed that the mechanism of penetration of SARS-CoV-2 and lysis of type II alveolocytes is the binding of the spike S-glycoprotein or capsid protein M of the virus to the receptor-binding domain of ACE2 on the surface of epithelial cells. Migration and infiltration of inflammatory cells leads to overactivation of TLR4 on the surface of alveolocytes and bronchial epithelium, shifting the process to MyD88-dependent acute inflammatory signaling and hypersecretion of proinflammatory cytokines that cause a “cytokine storm” and the development of severe complications of COVID-19 infection, in particular, acute respiratory infections, respiratory distress syndrome, pathology of internal organs, and, in some cases, the death of the patient. Conclusion. It is possible to suggest that TLRs have an impact on the immune response in COVID19 infection. Both antagonists and agonists of TLRs, depending on their type, can be examined to determine the therapeutic and negative effects of COVID-19 infection. Further research is needed to investigate TLRs and pathways for activating cytokine expression, as they indicate a direct relationship with mortality and virus susceptibility. Bioinformatic research can also help to better understand the interaction of TLRs with proteins and RNA of the SARS-CoV-2.

иммунитетпатогенез COVID‐19 инфекцияToll-подобные рецепторыimmunitypathogenesis of COVID-19 infectionToll-like receptorsReferencesHanaei S., Rezaei N. COVID-19: Developing from an Outbreak to A Pandemic // Arch. Med. Res. 2020. Vol.51, №6. P.582–584. https://doi.org/10.1016/j.arcmed.2020.04.021Hanaei S., Rezaei N. COVID-19: Developing from an Outbreak to A Pandemic // Arch. Med. Res. 2020. Vol.51, №6. P.582–584. https://doi.org/10.1016/j.arcmed.2020.04.021Birra D., Benucci M., Landolfi L., Merchionda A., Loi G., Amato P., Licata G., Quartuccio L., Triggiani M., Moscato P. COVID 19: a clue from innate immunity // Immunol. Res. 2020. Vol.68, №3. P.161–168. https://doi.org/10.1007/s12026-020-09137-5Birra D., Benucci M., Landolfi L., Merchionda A., Loi G., Amato P., Licata G., Quartuccio L., Triggiani M., Moscato P. COVID 19: a clue from innate immunity // Immunol. Res. 2020. Vol.68, №3. P.161–168. https://doi.org/10.1007/s12026-020-09137-5Debnath M., Banerjee M., Berk M. Genetic gateways to COVID-19 infection: Implications for risk, severity, and outcomes // FASEB J. 2020. Vol.34, №7. P.8787–8795. https://doi.org/10.1096/fj.202001115RDebnath M., Banerjee M., Berk M. Genetic gateways to COVID-19 infection: Implications for risk, severity, and outcomes // FASEB J. 2020. Vol.34, №7. P.8787–8795. https://doi.org/10.1096/fj.202001115RLester S.N., Li K. Toll-like receptors in antiviral innate immunity // J. Mol. Biol. 2014. Vol.426, №6. Р.1246–1264. https://doi.org/10.1016/j.jmb.2013.11.024Lester S.N., Li K. Toll-like receptors in antiviral innate immunity // J. Mol. Biol. 2014. Vol.426, №6. Р.1246–1264. https://doi.org/10.1016/j.jmb.2013.11.024Tian S., Hu W., Niu L., Liu H., Xu H., Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer // J. Thorac. Oncol. 2020. Vol.15, №5. Р.700–704. https://doi.org/10.1016/j.jtho.2020.02.010Tian S., Hu W., Niu L., Liu H., Xu H., Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer // J. Thorac. Oncol. 2020. Vol.15, №5. Р.700–704. https://doi.org/10.1016/j.jtho.2020.02.010Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., Liu S., Zhao P., Liu H., Zhu L., Tai Y., Bai C., Gao T., Song J., Xia P., Dong J., Zhao J., & Wang F.S. Pathological findings of COVID-19 associated with acute respiratory distress syndrome // The Lancet Respir. Med. 2020. Vol.8, №4. Р.420–422. https://doi.org/10.1016/S2213-2600(20)30076-XXu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., Liu S., Zhao P., Liu H., Zhu L., Tai Y., Bai C., Gao T., Song J., Xia P., Dong J., Zhao J., & Wang F.S. Pathological findings of COVID-19 associated with acute respiratory distress syndrome // The Lancet Respir. Med. 2020. Vol.8, №4. Р.420–422. https://doi.org/10.1016/S2213-2600(20)30076-XGeng Y.J., Wei Z.Y., Qian H.Y., Huang J., Lodato R., Castriotta R.J. Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019 // Cardiovasc. Pathol. 2020. Vol.47. Article number: 107228. https://doi.org/10.1016/j.carpath.2020.107228Geng Y.J., Wei Z.Y., Qian H.Y., Huang J., Lodato R., Castriotta R.J. Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019 // Cardiovasc. Pathol. 2020. Vol.47. Article number: 107228. https://doi.org/10.1016/j.carpath.2020.107228Su H., Yang M., Wan C., Yi L.X., Tang F., Zhu H.Y., Yi F., Yang H.C., Fogo A.B., Nie X., Zhang C. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China // Kidney Int. 2020. Vol.98, №1. Р.219–227. https://doi.org/10.1016/j.kint.2020.04.003Su H., Yang M., Wan C., Yi L.X., Tang F., Zhu H.Y., Yi F., Yang H.C., Fogo A.B., Nie X., Zhang C. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China // Kidney Int. 2020. Vol.98, №1. Р.219–227. https://doi.org/10.1016/j.kint.2020.04.003Batlle D., Soler M.J., Sparks M.A., Hiremath S., South A.M., Welling P.A., Swaminathan S. Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology // J. Am. Soc. Nephrol. 2020, Vol.31, №7. Р.1380–1383. https://doi.org/10.1681/ASN.2020040419Batlle D., Soler M.J., Sparks M.A., Hiremath S., South A.M., Welling P.A., Swaminathan S. Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology // J. Am. Soc. Nephrol. 2020, Vol.31, №7. Р.1380–1383. https://doi.org/10.1681/ASN.2020040419Gutiérrez-Ortiz C., Méndez-Guerrero A., Rodrigo-Rey S., San Pedro-Murillo E., Bermejo-Guerrero L., GordoMañas R., de Aragón-Gómez F., Benito-León J. Miller Fisher syndrome and polyneuritis cranialis in COVID-19 // Neurology. 2020. Vol.95, №5. Р.601–605. https://doi.org/10.1212/WNL.0000000000009619Gutiérrez-Ortiz C., Méndez-Guerrero A., Rodrigo-Rey S., San Pedro-Murillo E., Bermejo-Guerrero L., GordoMañas R., de Aragón-Gómez F., Benito-León J. Miller Fisher syndrome and polyneuritis cranialis in COVID-19 // Neurology. 2020. Vol.95, №5. Р.601–605. https://doi.org/10.1212/WNL.0000000000009619Zhao H., Shen D., Zhou H., Liu J., Chen S. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? // Lancet Neurol. 2020. Vol.19, №5. Р.383–384. https://doi.org/10.1016/S1474-4422(20)30109-5Zhao H., Shen D., Zhou H., Liu J., Chen S. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? // Lancet Neurol. 2020. Vol.19, №5. Р.383–384. https://doi.org/10.1016/S1474-4422(20)30109-5Al Saiegh F., Ghosh R., Leibold A., Avery M.B., Schmidt R.F., Theofanis T., Mouchtouris N., Philipp L., Peiper S.C., Wang Z.X., Rincon F., Tjoumakaris S.I., Jabbour P., Rosenwasser R.H., Gooch M.R. Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke // J. Neurol. Neurosurg. Psychiatry. 2020. Vol.91, №8. Р.846–848. https://doi.org/10.1136/jnnp-2020-323522Al Saiegh F., Ghosh R., Leibold A., Avery M.B., Schmidt R.F., Theofanis T., Mouchtouris N., Philipp L., Peiper S.C., Wang Z.X., Rincon F., Tjoumakaris S.I., Jabbour P., Rosenwasser R.H., Gooch M.R. Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke // J. Neurol. Neurosurg. Psychiatry. 2020. Vol.91, №8. Р.846–848. https://doi.org/10.1136/jnnp-2020-323522He X., Qian Y., Li Z., Fan E.K., Li Y., Wu L., Billiar T.R., Wilson M.A., Shi X., Fan J. TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism // Sci. Rep. 2016. Vol.6. Article number: 31663. https://doi.org/10.1038/srep31663He X., Qian Y., Li Z., Fan E.K., Li Y., Wu L., Billiar T.R., Wilson M.A., Shi X., Fan J. TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism // Sci. Rep. 2016. Vol.6. Article number: 31663. https://doi.org/10.1038/srep31663Mason R.J. Thoughts on the alveolar phase of COVID-19 // Am. J. Physiol. Lung Cell. Mol. Physiol. 2020. Vol.319, №1. Р.115–120. https://doi.org/10.1152/ajplung.00126.2020Mason R.J. Thoughts on the alveolar phase of COVID-19 // Am. J. Physiol. Lung Cell. Mol. Physiol. 2020. Vol.319, №1. Р.115–120. https://doi.org/10.1152/ajplung.00126.2020de Rivero Vaccari J.C., Dietrich W.D., Keane R.W., de Rivero Vaccari J.P. The Inflammasome in Times of COVID19 // Front. Immunol. 2020. Vol.8, №11. Article number: 583373. https://doi.org/10.3389/fimmu.2020.583373de Rivero Vaccari J.C., Dietrich W.D., Keane R.W., de Rivero Vaccari J.P. The Inflammasome in Times of COVID19 // Front. Immunol. 2020. Vol.8, №11. Article number: 583373. https://doi.org/10.3389/fimmu.2020.583373Khanmohammadi S., Rezaei N. Role of Toll-like receptors in the pathogenesis of COVID-19 // J. Med. Virol. 2021. Vol.93, №5. Р.2735–2739. https://doi.org/10.1002/jmv.26826Khanmohammadi S., Rezaei N. Role of Toll-like receptors in the pathogenesis of COVID-19 // J. Med. Virol. 2021. Vol.93, №5. Р.2735–2739. https://doi.org/10.1002/jmv.26826Lotfi M., Rezaei N. SARS-CoV-2: A comprehensive review from pathogenicity of the virus to clinical consequences // J. Med. Virol. 2020. Vol.92, №10. Р.1864–1874. https://doi.org/10.1002/jmv.26123Lotfi M., Rezaei N. SARS-CoV-2: A comprehensive review from pathogenicity of the virus to clinical consequences // J. Med. Virol. 2020. Vol.92, №10. Р.1864–1874. https://doi.org/10.1002/jmv.26123Alnefaie A., Albogami S. Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective // Saudi Pharm. J. 2020. Vol.28, №11. Р.1333–1352. https://doi.org/10.1016/j.jsps.2020.08.024Alnefaie A., Albogami S. Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective // Saudi Pharm. J. 2020. Vol.28, №11. Р.1333–1352. https://doi.org/10.1016/j.jsps.2020.08.024Saghazadeh A., Rezaei N. Implications of Toll-like receptors in Ebola infection // Expert Opin. Ther. Targets. 2017. Vol.21, №4. Р.415–425. https://doi.org/10.1080/14728222.2017.1299128Saghazadeh A., Rezaei N. Implications of Toll-like receptors in Ebola infection // Expert Opin. Ther. Targets. 2017. Vol.21, №4. Р.415–425. https://doi.org/10.1080/14728222.2017.1299128Florindo H.F., Kleiner R., Vaskovich-Koubi D., Acúrcio R.C., Carreira B., Yeini E., Tiram G., Liubomirski Y., Satchi-Fainaro R. Immune-mediated approaches against COVID-19 // Nat. Nanotechnol. 2020. Vol.15, №8. Р.630–645. https://doi.org/10.1038/s41565-020-0732-3Florindo H.F., Kleiner R., Vaskovich-Koubi D., Acúrcio R.C., Carreira B., Yeini E., Tiram G., Liubomirski Y., Satchi-Fainaro R. Immune-mediated approaches against COVID-19 // Nat. Nanotechnol. 2020. Vol.15, №8. Р.630–645. https://doi.org/10.1038/s41565-020-0732-3Conti P., Ronconi G., Caraffa A., Gallenga C.E., Ross R., Frydas I., Kritas S.K. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies // J. Biol. Regul. Homeost. Agents. 2020. Vol.34, №2. Р.327–331 https://doi.org/10.23812/CONTI-EConti P., Ronconi G., Caraffa A., Gallenga C.E., Ross R., Frydas I., Kritas S.K. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies // J. Biol. Regul. Homeost. Agents. 2020. Vol.34, №2. Р.327–331 https://doi.org/10.23812/CONTI-EPatra R., Chandra Das N., Mukherjee S. Targeting human TLRs to combat COVID-19: A solution? // J. Med. Virol. 2021. Vol.93, №2. Р.615–617. https://doi.org/10.1002/jmv.26387Patra R., Chandra Das N., Mukherjee S. Targeting human TLRs to combat COVID-19: A solution? // J. Med. Virol. 2021. Vol.93, №2. Р.615–617. https://doi.org/10.1002/jmv.26387Totura A.L., Whitmore A., Agnihothram S., Schäfer A., Katze M.G., Heise M.T., Baric R.S. Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection // mBio. 2015. Vol.26, №6. e00638-15. https://doi.org/10.1128/mBio.00638-15Totura A.L., Whitmore A., Agnihothram S., Schäfer A., Katze M.G., Heise M.T., Baric R.S. Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection // mBio. 2015. Vol.26, №6. e00638-15. https://doi.org/10.1128/mBio.00638-15Cicco S., Cicco G., Racanelli V., Vacca A. Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment // Mediators Inflamm. 2020. Vol.2020. Article ID 7527953. https://doi.org/10.1155/2020/7527953Cicco S., Cicco G., Racanelli V., Vacca A. Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment // Mediators Inflamm. 2020. Vol.2020. Article ID 7527953. https://doi.org/10.1155/2020/7527953Khadke S., Ahmed N., Ahmed N., Ratts R., Raju S., Gallogly M., de Lima M., Sohail M.R. Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents // Virol. J. 2020. Vol.17, №1. Article number: 154. https://doi.org/10.1186/s12985-020-01415-wKhadke S., Ahmed N., Ahmed N., Ratts R., Raju S., Gallogly M., de Lima M., Sohail M.R. Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents // Virol. J. 2020. Vol.17, №1. Article number: 154. https://doi.org/10.1186/s12985-020-01415-wSohn K.M., Lee S.G., Kim H.J., Cheon S., Jeong H., Lee J., Kim I.S., Silwal P., Kim Y.J., Paik S., Chung C., Park C., Kim Y.S., Jo E.K. COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis // J. Korean Med. Sci. 2020. Vol.35, №38. Article number: e343. https://doi.org/10.3346/jkms.2020.35.e343Sohn K.M., Lee S.G., Kim H.J., Cheon S., Jeong H., Lee J., Kim I.S., Silwal P., Kim Y.J., Paik S., Chung C., Park C., Kim Y.S., Jo E.K. COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis // J. Korean Med. Sci. 2020. Vol.35, №38. Article number: e343. https://doi.org/10.3346/jkms.2020.35.e343Proud P.C., Tsitoura D., Watson R.J., Chua B.Y., Aram M.J., Bewley K.R., Cavell B.E., Cobb R., Dowall S., Fotheringham S.A., Ho CM.K., Lucas V., Ngabo D., Rayner E., Ryan K.A., Slack G.S., Thomas S., Wand N.I., Yeates P., Demaison C., Zeng W., Holmes I., Jackson D.C., Bartlett N.W., Mercuri F., Carroll M.W. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model // EBioMedicine. 2021. Vol.63. Article number: 103153. https://doi.org/10.1016/j.ebiom.2020.103153Proud P.C., Tsitoura D., Watson R.J., Chua B.Y., Aram M.J., Bewley K.R., Cavell B.E., Cobb R., Dowall S., Fotheringham S.A., Ho CM.K., Lucas V., Ngabo D., Rayner E., Ryan K.A., Slack G.S., Thomas S., Wand N.I., Yeates P., Demaison C., Zeng W., Holmes I., Jackson D.C., Bartlett N.W., Mercuri F., Carroll M.W. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model // EBioMedicine. 2021. Vol.63. Article number: 103153. https://doi.org/10.1016/j.ebiom.2020.103153de Groot N.G., Bontrop R.E. COVID-19 pandemic: is a gender-defined dosage effect responsible for the high mortality rate among males? // Immunogenetics. 2020. Vol.72, №5. Р.275–277. https://doi.org/10.1007/s00251-020-01165-7de Groot N.G., Bontrop R.E. COVID-19 pandemic: is a gender-defined dosage effect responsible for the high mortality rate among males? // Immunogenetics. 2020. Vol.72, №5. Р.275–277. https://doi.org/10.1007/s00251-020-01165-7Yazdanpanah F., Hamblin M.R., Rezaei N. The immune system and COVID-19: Friend or foe? // Life Sci. 2020. Vol.256. Article number: 117900. https://doi.org/10.1016/j.lfs.2020.117900Yazdanpanah F., Hamblin M.R., Rezaei N. The immune system and COVID-19: Friend or foe? // Life Sci. 2020. Vol.256. Article number: 117900. https://doi.org/10.1016/j.lfs.2020.117900Choudhury A., Mukherjee S. In silico studies on the comparative characterization of the interactions of SARSCoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs // J. Med. Virol. 2020. Vol.92, №10. Р.2105– 2113. https://doi.org/10.1002/jmv.25987Choudhury A., Mukherjee S. In silico studies on the comparative characterization of the interactions of SARSCoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs // J. Med. Virol. 2020. Vol.92, №10. Р.2105– 2113. https://doi.org/10.1002/jmv.25987Autilio C., Echaide M., Cruz A., García-Mouton C., Hidalgo A., Da Silva E., De Luca D., Sørli J.B., Pérez-Gil J. Molecular and biophysical mechanisms behind the enhancement of lung surfactant function during controlled therapeutic hypothermia // Sci. Rep. 2021. Vol.11, №1. Article number: 728. https://doi.org/10.1038/s41598-020-79025-3Autilio C., Echaide M., Cruz A., García-Mouton C., Hidalgo A., Da Silva E., De Luca D., Sørli J.B., Pérez-Gil J. Molecular and biophysical mechanisms behind the enhancement of lung surfactant function during controlled therapeutic hypothermia // Sci. Rep. 2021. Vol.11, №1. Article number: 728. https://doi.org/10.1038/s41598-020-79025-3Słońska A., Cymerys J., Bańbura M.W. Mechanisms of endocytosis utilized by viruses during infection // Postepy Hig. Med. Dosw. (Online). 2016. Vol.70, №1. Р.572–580. https://doi.org/10.5604/17322693.1203721Słońska A., Cymerys J., Bańbura M.W. Mechanisms of endocytosis utilized by viruses during infection // Postepy Hig. Med. Dosw. (Online). 2016. Vol.70, №1. Р.572–580. https://doi.org/10.5604/17322693.1203721Wu Y., Xu X., Chen Z. Nervous system involvement after infection with COVID-19 and other coronaviruses // Brain Behav. Immun. 2020. Vol.87, №1. Р.18–22. https://doi.org/10.1016/j.bbi.2020.03.031Wu Y., Xu X., Chen Z. Nervous system involvement after infection with COVID-19 and other coronaviruses // Brain Behav. Immun. 2020. Vol.87, №1. Р.18–22. https://doi.org/10.1016/j.bbi.2020.03.031Zheng M., Karki R., Williams E.P. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines // Nat. Immunol. 2021. Vol.22, №7. Р.829–838. https://doi.org/10.1038/s41590-021-00937-xZheng M., Karki R., Williams E.P. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines // Nat. Immunol. 2021. Vol.22, №7. Р.829–838. https://doi.org/10.1038/s41590-021-00937-x

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