IMMUNE NETWORK

  • 제21권1호
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  • Pages.3.1-3.16
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  • 2021
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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SARS-CoV-2 Infection of Airway Epithelial Cells

  • Gwanghui Ryu (Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine) ;
  • Hyun-Woo Shin (Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine)
  • 투고 : 2021.01.09
  • 심사 : 2021.02.17
  • 발행 : 2021.02.28
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초록

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide since its outbreak in December 2019, and World Health Organization declared it as a pandemic on March 11, 2020. SARS-CoV-2 is highly contagious and is transmitted through airway epithelial cells as the first gateway. SARS-CoV-2 is detected by nasopharyngeal or oropharyngeal swab samples, and the viral load is significantly high in the upper respiratory tract. The host cellular receptors in airway epithelial cells, including angiotensin-converting enzyme 2 and transmembrane serine protease 2, have been identified by single-cell RNA sequencing or immunostaining. The expression levels of these molecules vary by type, function, and location of airway epithelial cells, such as ciliated cells, secretory cells, olfactory epithelial cells, and alveolar epithelial cells, as well as differ from host to host depending on age, sex, or comorbid diseases. Infected airway epithelial cells by SARS-CoV-2 in ex vivo experiments produce chemokines and cytokines to recruit inflammatory cells to target organs. Same as other viral infections, IFN signaling is a critical pathway for host defense. Various studies are underway to confirm the pathophysiological mechanisms of SARS-CoV-2 infection. Herein, we review cellular entry, host-viral interactions, immune responses to SARS-CoV-2 in airway epithelial cells. We also discuss therapeutic options related to epithelial immune reactions to SARS-CoV-2.

키워드

과제정보

This work was supported by a grant from the National Research Foundation of Korea (2020R1A4A2002903 to H.W.S. and 2020R1I1A3075353 to G.R.) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant No. HI17C1669). This work was supported by the Soonchunhyang University Research Fund.

참고문헌

  1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-1069. https://doi.org/10.1001/jama.2020.1585
  2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-733. https://doi.org/10.1056/NEJMoa2001017
  3. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020;579:265-269. https://doi.org/10.1038/s41586-020-2008-3
  4. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-273. https://doi.org/10.1038/s41586-020-2012-7
  5. Larsen JR, Martin MR, Martin JD, Kuhn P, Hicks JB. Modeling the onset of symptoms of COVID-19. Front Public Health 2020;8:473.
  6. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395:1607-1608. https://doi.org/10.1016/S0140-6736(20)31094-1
  7. Richard M, Kok A, de Meulder D, Bestebroer TM, Lamers MM, Okba NMA, Fentener van Vlissingen M, Rockx B, Haagmans BL, Koopmans MPG, et al. SARS-CoV-2 is transmitted via contact and via the air between ferrets. Nat Commun 2020;11:3496.
  8. Zhang R, Li Y, Zhang AL, Wang Y, Molina MJ. Identifying airborne transmission as the dominant route for the spread of COVID-19. Proc Natl Acad Sci U S A 2020;117:14857-14863. https://doi.org/10.1073/pnas.2009637117
  9. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179. https://doi.org/10.1056/NEJMc2001737
  10. Vlek ALM, Wesselius TS, Achterberg R, Thijsen SFT. Combined throat/nasal swab sampling for SARS-CoV-2 is equivalent to nasopharyngeal sampling. Eur J Clin Microbiol Infect Dis 2021;40:193-195. https://doi.org/10.1007/s10096-020-03972-y
  11. Wang H, Liu Q, Hu J, Zhou M, Yu MQ, Li KY, Xu D, Xiao Y, Yang JY, Lu YJ, et al. Nasopharyngeal swabs are more sensitive than oropharyngeal swabs for COVID-19 diagnosis and monitoring the SARS-CoV-2 load. Front Med (Lausanne) 2020;7:334.
  12. Sungnak W, Huang N, Becavin C, Berg M, Queen R, Litvinukova M, Talavera-Lopez C, Maatz H, Reichart D, Sampaziotis F, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 2020;26:681-687. https://doi.org/10.1038/s41591-020-0868-6
  13. Fung M, Otani I, Pham M, Babik J. Zoonotic coronavirus epidemics: SARS, MERS, and COVID-19. Ann Allergy Asthma Immunol 2020. doi: 10.1016/j.anai.2020.11.021.
  14. Peiris JS, Yuen KY, Osterhaus AD, Stohr K. The severe acute respiratory syndrome. N Engl J Med 2003;349:2431-2441. https://doi.org/10.1056/NEJMra032498
  15. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454. https://doi.org/10.1038/nature02145
  16. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-280.e8. https://doi.org/10.1016/j.cell.2020.02.052
  17. Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, Perin P, Lucas JM, Nelson PS, Pohlmann S, Soilleux EJ. Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS One 2012;7:e35876.
  18. Du M, Cai G, Chen F, Christiani DC, Zhang Z, Wang M. Multiomics evaluation of gastrointestinal and other clinical characteristics of COVID-19. Gastroenterology 2020;158:2298-2301.e7. https://doi.org/10.1053/j.gastro.2020.03.045
  19. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-1263. https://doi.org/10.1126/science.abb2507
  20. Gallo O, Locatello LG, Mazzoni A, Novelli L, Annunziato F. The central role of the nasal microenvironment in the transmission, modulation, and clinical progression of SARS-CoV-2 infection. Mucosal Immunol 2020. doi: 10.1038/s41385-020-00359-2.
  21. Bedford J, Enria D, Giesecke J, Heymann DL, Ihekweazu C, Kobinger G, Lane HC, Memish Z, Oh MD, Sall AA, et al. COVID-19: towards controlling of a pandemic. Lancet 2020;395:1015-1018. https://doi.org/10.1016/S0140-6736(20)30673-5
  22. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020;583:459-468. https://doi.org/10.1038/s41586-020-2286-9
  23. Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res 2016;118:1313-1326. https://doi.org/10.1161/CIRCRESAHA.116.307708
  24. Lee IT, Nakayama T, Wu CT, Goltsev Y, Jiang S, Gall PA, Liao CK, Shih LC, Schurch CM, McIlwain DR, et al. ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nat Commun 2020;11:5453.
  25. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436:112-116. https://doi.org/10.1038/nature03712
  26. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-879. https://doi.org/10.1038/nm1267
  27. Huang F, Guo J, Zou Z, Liu J, Cao B, Zhang S, Li H, Wang W, Sheng M, Liu S, et al. Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients. Nat Commun 2014;5:3595.
  28. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-1448. https://doi.org/10.1126/science.abb2762
  29. Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013;495:251-254. https://doi.org/10.1038/nature12005
  30. Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020;181:1016-1035.e19. https://doi.org/10.1016/j.cell.2020.04.035
  31. Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, Vinarsky V, Cho JL, Breton S, Sahay A, et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 2013;503:218-223. https://doi.org/10.1038/nature12777
  32. Chen M, Shen W, Rowan NR, Kulaga H, Hillel A, Ramanathan M Jr, Lane AP. Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J 2020;56:2001948.
  33. Chua RL, Lukassen S, Trump S, Hennig BP, Wendisch D, Pott F, Debnath O, Thurmann L, Kurth F, Volker MT, et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat Biotechnol 2020;38:970-979. https://doi.org/10.1038/s41587-020-0602-4
  34. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020;176:104742.
  35. Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, Winter H, Meister M, Veith C, Boots AW, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J 2020;39:e105114.
  36. Aguiar JA, Tremblay BJ, Mansfield MJ, Woody O, Lobb B, Banerjee A, Chandiramohan A, Tiessen N, Cao Q, Dvorkin-Gheva A, et al. Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue. Eur Respir J 2020;56:2001123.
  37. Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020;370:856-860.
  38. Daly JL, Simonetti B, Klein K, Chen KE, Williamson MK, Anton-Plagaro C, Shoemark DK, Simon-Gracia L, Bauer M, Hollandi R, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 2020;370:861-865. https://doi.org/10.1126/science.abd3072
  39. Drozdzal S, Rosik J, Lechowicz K, Machaj F, Kotfis K, Ghavami S, Los MJ. FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy. Drug Resist Updat 2020;53:100719.
  40. Milewska A, Kula-Pacurar A, Wadas J, Suder A, Szczepanski A, Dabrowska A, Owczarek K, Marcello A, Ochman M, Stacel T, et al. Replication of severe acute respiratory syndrome coronavirus 2 in human respiratory epithelium. J Virol 2020;94:e00957-20.
  41. Sallenave JM, Guillot L. Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in COVID-19: key therapeutic targets? Front Immunol 2020;11:1229.
  42. Fiege JK, Thiede JM, Nanda HA, Matchett WE, Moore PJ, Montanari NR, Thielen BK, Daniel J, Stanley E, Hunter RC, et al. Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium. PLoS Pathog 2021;17:e1009292.
  43. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-637.
  44. Harcourt J, Tamin A, Lu X, Kamili S, Sakthivel SK, Murray J, Queen K, Tao Y, Paden CR, Zhang J, et al. Severe acute respiratory syndrome coronavirus 2 from patient with coronavirus disease, united states. Emerg Infect Dis 2020;26:1266-1273. https://doi.org/10.3201/eid2606.200516
  45. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, Jordan TX, Oishi K, Panis M, Sachs D, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020;181:1036-1045.e9.
  46. Gamage AM, Tan KS, Chan WO, Liu J, Tan CW, Ong YK, Thong M, Andiappan AK, Anderson DE, Wang Y, et al. Infection of human nasal epithelial cells with SARS-CoV-2 and a 382-nt deletion isolate lacking ORF8 reveals similar viral kinetics and host transcriptional profiles. PLoS Pathog 2020;16:e1009130.
  47. Zhu N, Wang W, Liu Z, Liang C, Wang W, Ye F, Huang B, Zhao L, Wang H, Zhou W, et al. Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells. Nat Commun 2020;11:3910.
  48. Hao S, Ning K, Kuz CA, Vorhies K, Yan Z, Qiu J. Long-term modeling of SARS-CoV-2 infection of in vitro cultured polarized human airway epithelium. MBio 2020;11:e02852-20.
  49. Ehre C. SARS-CoV-2 infection of airway cells. N Engl J Med 2020;383:969.
  50. Ravindra NG, Alfajaro MM, Gasque V, Wei J, Filler RB, Huston NC, Wan H, Szigeti-Buck K, Wang B, Montgomery RR, et al. Single-cell longitudinal analysis of SARS-CoV-2 infection in human bronchial epithelial cells. bioRxiv 2020. doi: 10.1101/2020.05.06.081695.
  51. Xie X, Muruato A, Lokugamage KG, Narayanan K, Zhang X, Zou J, Liu J, Schindewolf C, Bopp NE, Aguilar PV, et al. An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe 2020;27:841-848.e3. https://doi.org/10.1016/j.chom.2020.04.004
  52. Lamers MM, van der Vaart J, Knoops K, Riesebosch S, Breugem TI, Mykytyn AZ, Beumer J, Schipper D, Bezstarosti K, Koopman CD, et al. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J 2020. doi: 10.15252/embj.2020105912.
  53. Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, Ravelli RB, Paul van Schayck J, Mykytyn AZ, Duimel HQ, et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020;369:50-54.
  54. Salahudeen AA, Choi SS, Rustagi A, Zhu J, van Unen V, de la O SM, Flynn RA, Margalef-Catala M, Santos AJ, Ju J, et al. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature 2020;588:670-675.
  55. Han Y, Duan X, Yang L, Nilsson-Payant BE, Wang P, Duan F, Tang X, Yaron TM, Zhang T, Uhl S, et al. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 2021;589:270-275. https://doi.org/10.1038/s41586-020-2901-9
  56. Mulay A, Konda B, Garcia G, Yao C, Beil S, Sen C, Purkayastha A, Kolls JK, Pociask DA, Pessina P, et al. SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery. bioRxiv 2020. doi: 10.1101/2020.06.29.174623.
  57. Matheson NJ, Lehner PJ. How does SARS-CoV-2 cause COVID-19? Science 2020;369:510-511. https://doi.org/10.1126/science.abc6156
  58. Yao Y, Wang H, Liu Z. Expression of ACE2 in airways: Implication for COVID-19 risk and disease management in patients with chronic inflammatory respiratory diseases. Clin Exp Allergy 2020;50:1313-1324. https://doi.org/10.1111/cea.13746
  59. Saheb Sharif-Askari N, Saheb Sharif-Askari F, Alabed M, Temsah MH, Al Heialy S, Hamid Q, Halwani R. Airways expression of SARS-CoV-2 receptor, ACE2, and TMPRSS2 is lower in children than adults and increases with smoking and COPD. Mol Ther Methods Clin Dev 2020;18:1-6. https://doi.org/10.1016/j.omtm.2020.05.013
  60. Bunyavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA 2020;323:2427-2429. https://doi.org/10.1001/jama.2020.8707
  61. Schouten LR, van Kaam AH, Kohse F, Veltkamp F, Bos LD, de Beer FM, van Hooijdonk RT, Horn J, Straat M, Witteveen E, et al. Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study. Ann Intensive Care 2019;9:55.
  62. Ortiz ME, Thurman A, Pezzulo AA, Leidinger MR, Klesney-Tait JA, Karp PH, Tan P, Wohlford-Lenane C, McCray PB Jr, Meyerholz DK. Heterogeneous expression of the SARS-coronavirus-2 receptor ACE2 in the human respiratory tract. EBioMedicine 2020;60:102976.
  63. Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med 2021;27:28-33. https://doi.org/10.1038/s41591-020-01202-8
  64. Bajaj V, Gadi N, Spihlman AP, Wu SC, Choi CH, Moulton VR. Aging, immunity, and COVID-19: how age influences the host immune response to coronavirus infections? Front Physiol 2021;11:571416.
  65. Inde Z, Yapp C, Joshi GN, Spetz J, Fraser C, Deskin B, Ghelfi E, Sodhi C, Hackam D, Kobzik L, et al. Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 disease severity. bioRxiv 2020. doi: 10.1101/2020.09.13.276923.
  66. Meftahi GH, Jangravi Z, Sahraei H, Bahari Z. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging". Inflamm Res 2020;69:825-839. https://doi.org/10.1007/s00011-020-01372-8
  67. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000;87:E1-E9.
  68. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002;417:822-828.
  69. Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, Timens W, Turner AJ, Navis G, van Goor H. The emerging role of ACE2 in physiology and disease. J Pathol 2007;212:1-11. https://doi.org/10.1002/path.2162
  70. Zhang H, Rostami MR, Leopold PL, Mezey JG, O'Beirne SL, Strulovici-Barel Y, Crystal RG. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium. Am J Respir Crit Care Med 2020;202:219-229. https://doi.org/10.1164/rccm.202003-0541OC
  71. Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, Singhera GK, Dorscheid DR, Sin DD. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J 2020;55:55.
  72. Purkayastha A, Sen C, Garcia G Jr, Langerman J, Shia DW, Meneses LK, Vijayaraj P, Durra A, Koloff CR, Freund DR, et al. Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response. Cell Stem Cell 2020;27:869-875.e4. https://doi.org/10.1016/j.stem.2020.11.010
  73. Kimura H, Francisco D, Conway M, Martinez FD, Vercelli D, Polverino F, Billheimer D, Kraft M. Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells. J Allergy Clin Immunol 2020;146:80-88.e8. https://doi.org/10.1016/j.jaci.2020.05.004
  74. Sajuthi SP, DeFord P, Li Y, Jackson ND, Montgomery MT, Everman JL, Rios CL, Pruesse E, Nolin JD, Plender EG, et al. Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. Nat Commun 2020;11:5139.
  75. Jackson DJ, Busse WW, Bacharier LB, Kattan M, O'Connor GT, Wood RA, Visness CM, Durham SR, Larson D, Esnault S, et al. Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2. J Allergy Clin Immunol 2020;146:203-206.e3. https://doi.org/10.1016/j.jaci.2020.04.009
  76. Wang M, Wang C, Zhang L. Inflammatory endotypes of CRSwNP and responses to COVID-19. Curr Opin Allergy Clin Immunol 2021;21:8-15. https://doi.org/10.1097/ACI.0000000000000700
  77. Wang H, Song J, Pan L, Deng YK, Yao Y, Wang ZC, Liao B, Ma J, Zeng M, Liu Z. Regional differences in ACE2 expression in the sinonasal mucosa of adult Chinese patients with chronic rhinosinusitis. Allergy 2020. doi: 10.1111/all.14623.
  78. Wang M, Bu X, Fang G, Luan G, Huang Y, Akdis CA, Wang C, Zhang L. Distinct expression of SARS-CoV-2 receptor ACE2 correlates with endotypes of chronic rhinosinusitis with nasal polyps. Allergy 2020. doi: 10.1111/all.14665.
  79. Narasaraju T. Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19. Ann Intern Med 2020;173:323-324. https://doi.org/10.7326/L20-0894
  80. Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the nlrp3 inflammasome. Front Microbiol 2019;10:50.
  81. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 2005;73:1907-1916. https://doi.org/10.1128/IAI.73.4.1907-1916.2005
  82. Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-374. https://doi.org/10.1038/s41577-020-0311-8
  83. Lazear HM, Schoggins JW, Diamond MS. Shared and distinct functions of type i and type iii interferons. Immunity 2019;50:907-923. https://doi.org/10.1016/j.immuni.2019.03.025
  84. Hur S. Double-stranded RNA sensors and modulators in innate immunity. Annu Rev Immunol 2019;37:349-375. https://doi.org/10.1146/annurev-immunol-042718-041356
  85. Sokol CL, Luster AD. The chemokine system in innate immunity. Cold Spring Harb Perspect Biol 2015;7:a016303.
  86. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Pere H, Charbit B, Bondet V, Chenevier-Gobeaux C, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718-724. https://doi.org/10.1126/science.abc6027
  87. Arunachalam PS, Wimmers F, Mok CKP, Perera RA, Scott M, Hagan T, Sigal N, Feng Y, Bristow L, Tak-Yin Tsang O, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 2020;369:1210-1220. https://doi.org/10.1126/science.abc6261
  88. Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, Ellingson MK, Mao T, Oh JE, Israelow B, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020;584:463-469. https://doi.org/10.1038/s41586-020-2588-y
  89. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020;368:473-474. https://doi.org/10.1126/science.abb8925
  90. Sa Ribero M, Jouvenet N, Dreux M, Nisole S. Interplay between SARS-CoV-2 and the type I interferon response. PLoS Pathog 2020;16:e1008737.
  91. Bost P, Giladi A, Liu Y, Bendjelal Y, Xu G, David E, Blecher-Gonen R, Cohen M, Medaglia C, Li H, et al. Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell 2020;181:1475-1488.e12. https://doi.org/10.1016/j.cell.2020.05.006
  92. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Cheng L, Li J, Wang X, Wang F, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 2020;26:842-844. https://doi.org/10.1038/s41591-020-0901-9
  93. Lee JS, Park S, Jeong HW, Ahn JY, Choi SJ, Lee H, Choi B, Nam SK, Sa M, Kwon JS, 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:eabd1554.
  94. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020;130:2620-2629. https://doi.org/10.1172/JCI137244
  95. Hirano T, Murakami M. COVID-19: a new virus, but a familiar receptor and cytokine release syndrome. Immunity 2020;52:731-733. https://doi.org/10.1016/j.immuni.2020.04.003
  96. Zhuang MW, Cheng Y, Zhang J, Jiang XM, Wang L, Deng J, Wang PH. Increasing host cellular receptor-angiotensin-converting enzyme 2 expression by coronavirus may facilitate 2019-nCoV (or SARS-CoV-2) infection. J Med Virol 2020;92:2693-2701. https://doi.org/10.1002/jmv.26139
  97. Onabajo OO, Banday AR, Stanifer ML, Yan W, Obajemu A, Santer DM, Florez-Vargas O, Piontkivska H, Vargas JM, Ring TJ, et al. Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. Nat Genet 2020;52:1283-1293. https://doi.org/10.1038/s41588-020-00731-9
  98. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARSCoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020;46:586-590. https://doi.org/10.1007/s00134-020-05985-9
  99. Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020;181:905-913.e7. https://doi.org/10.1016/j.cell.2020.04.004
  100. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 2017;21:234.
  101. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care 2017;21:305.
  102. Wang K, Chen W, Zhang Z, Deng Y, Lian JQ, Du P, Wei D, Zhang Y, Sun XX, Gong L, et al. CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduct Target Ther 2020;5:283.
  103. Bian H, Zheng ZH, Wei D, Zhang Z, Kang WZ, Hao CQ, Dong K, Kang W, Xia JL, Miao JL, et al. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial. medRxiv 2020. doi: 10.1101/2020.03.21.20040691. .
  104. Lau SKP, Lau CCY, Chan KH, Li CPY, Chen H, Jin DY, Chan JFW, Woo PCY, Yuen KY. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol 2013;94:2679-2690. https://doi.org/10.1099/vir.0.055533-0
  105. Cameron MJ, Ran L, Xu L, Danesh A, Bermejo-Martin JF, Cameron CM, Muller MP, Gold WL, Richardson SE, Poutanen SM, et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol 2007;81:8692-8706.
  106. Felgenhauer U, Schoen A, Gad HH, Hartmann R, Schaubmar AR, Failing K, Drosten C, Weber F. Inhibition of SARS-CoV-2 by type I and type III interferons. J Biol Chem 2020;295:13958-13964. https://doi.org/10.1074/jbc.AC120.013788
  107. Lokugamage KG, Hage A, de Vries M, Valero-Jimenez AM, Schindewolf C, Dittmann M, Rajsbaum R, Menachery VD. Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV. J Virol 2020;94:e01410-20.
  108. Mantlo E, Bukreyeva N, Maruyama J, Paessler S, Huang C. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res 2020;179:104811.
  109. Andreakos E, Salagianni M, Galani IE, Koltsida O. Interferon-λs: front-line guardians of immunity and homeostasis in the respiratory tract. Front Immunol 2017;8:1232.
  110. Broggi A, Granucci F, Zanoni I. Type III interferons: balancing tissue tolerance and resistance to pathogen invasion. J Exp Med 2020;217:217.
  111. Prokunina-Olsson L, Alphonse N, Dickenson RE, Durbin JE, Glenn JS, Hartmann R, Kotenko SV, Lazear HM, O'Brien TR, Odendall C, et al. COVID-19 and emerging viral infections: the case for interferon lambda. J Exp Med 2020;217:217.
  112. Broggi A, Ghosh S, Sposito B, Spreafico R, Balzarini F, Lo Cascio A, Clementi N, De Santis M, Mancini N, Granucci F, et al. Type III interferons disrupt the lung epithelial barrier upon viral recognition. Science 2020;369:706-712.