SARS-CoV-2 Infection of Airway Epithelial Cells

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 Monica Fung, "Zoonotic coronavirus epidemics" Elsevier BV 126 (126): 321-337, 2021

2 Broggi A, "Type III interferons disrupt the lung epithelial barrier upon viral recognition" 369 : 706-712, 2020

3 Broggi A, "Type III interferons : balancing tissue tolerance and resistance to pathogen invasion" 217 : 217-, 2020

4 Lokugamage KG, "Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV" 94 : e01410-e01420, 2020

5 Kimura H, "Type 2inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells" 146 : 80.e8-88.e8, 2020

6 Sajuthi SP, "Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium" 11 : 5139-, 2020

7 Hamming I, "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis" 203 : 631-637, 2004

8 Tay MZ, "The trinity of COVID-19 : immunity, inflammation and intervention" 20 : 363-374, 2020

9 Coutard B, "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade" 176 : 104742-, 2020

10 Peiris JS, "The severe acute respiratory syndrome" 349 : 2431-2441, 2003

11 Meftahi GH, "The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection : the contribution of"inflame-aging"" 69 : 825-839, 2020

12 Hamming I, "The emerging role of ACE2 in physiology and disease" 212 : 1-11, 2007

13 Sokol CL, "The chemokine system in innate immunity" 7 : a016303-, 2015

14 Oreste Gallo, "The central role of the nasal microenvironment in the transmission, modulation, and clinical progression of SARS-CoV-2 infection" Springer Science and Business Media LLC 14 (14): 305-316, 2021

15 Arunachalam PS, "Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans" 369 : 1210-1220, 2020

16 Yan R, "Structural basis for the recognition of SARS-CoV-2 by fulllength human ACE2" 367 : 1444-1448, 2020

17 Ravindra NG, "Single-cell longitudinal analysis of SARS-CoV-2 infection in human bronchial epithelial cells"

18 Liao M, "Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19" 26 : 842-844, 2020

19 Fiege JK, "Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium" 17 : e1009292-, 2021

20 Lazear HM, "Shared and distinct functions of type i and type iii interferons" 50 : 907-923, 2019

21 Chen IY, "Severe acute respiratory syndrome coronavirus viroporin 3a activates the nlrp3 inflammasome" 10 : 50-, 2019

22 Harcourt J, "Severe acute respiratory syndrome coronavirus 2 from patient with coronavirus disease, united states" 26 : 1266-1273, 2020

23 Zou L, "SARS-CoV-2 viral load in upper respiratory specimens of infected patients" 382 : 1177-1179, 2020

24 Ziegler CGK, "SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues" 181 : 1016-1035, 2020

25 Lukassen S, "SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells" 39 : e105114-, 2020

26 Lamers MM, "SARS-CoV-2 productively infects human gut enterocytes" 369 : 50-54, 2020

27 Richard M, "SARS-CoV-2 is transmitted via contact and via the air between ferrets" 11 : 3496-, 2020

28 Mulay A, "SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery"

29 Ehre C, "SARS-CoV-2 infection of airway cells" 383 : 969-, 2020

30 Sungnak W, "SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes" 26 : 681-687, 2020

31 Hoffmann M, "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor" 181 : 271-280, 2020

32 Patel VB, "Role of the ACE2/angiotensin 1–7 axis of the renin-angiotensin system in heart failure" 118 : 1313-1326, 2016

33 Milewska A, "Replication of severe acute respiratory syndrome coronavirus 2 in human respiratory epithelium" 94 : e00957-20, 2020

34 Hai Wang, "Regional differences in ACE2 expression in the sinonasal mucosa of adult Chinese patients with chronic rhinosinusitis" Wiley 76 (76): 1565-1568, 2021

35 Zhang H, "Recombinant human ACE2 : acing out angiotensin II in ARDS therapy" 21 : 305-, 2017

36 Salahudeen AA, "Progenitor identification and SARS-CoV-2 infection in human distal lung organoids" 588 : 670-675, 2020

37 Daly JL, "Neuropilin-1 is a host factor for SARS-CoV-2 infection" 370 : 861-865, 2020

38 Cantuti-Castelvetri L, "Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity" 370 : 856-860, 2020

39 Wang H, "Nasopharyngeal swabs are more sensitive than oropharyngeal swabs for COVID-19 diagnosis and monitoring the SARS-CoV-2 load" 7 : 334-, 2020

40 Bunyavanich S, "Nasal gene expression of angiotensin-converting enzyme 2 in children and adults" 323 : 2427-2429, 2020

41 Du M, "Multiomics evaluation of gastrointestinal and other clinical characteristics of COVID-19" 158 : 2298.e7-2301.e7, 2020

42 Zhu N, "Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells" 11 : 3910-, 2020

43 Larsen JR, "Modeling the onset of symptoms of COVID-19" 8 : 473-, 2020

44 Bian H, "Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial"

45 Lucas C, "Longitudinal analyses reveal immunological misfiring in severe COVID-19" 584 : 463-469, 2020

46 Hao S, "Long-term modeling of SARS-CoV-2 infection of in vitro cultured polarized human airway epithelium" 11 : e02852-20, 2020

47 Sa Ribero M, "Interplay between SARS-CoV-2 and the type I interferon response" 16 : e1008737-, 2020

48 Onabajo OO, "Interferons and viruses induce a novel truncated ACE2 isoform and not the fulllength SARS-CoV-2 receptor" 52 : 1283-1293, 2020

49 Andreakos E, "Interferon-λs : front-line guardians of immunity and homeostasis in the respiratory tract" 8 : 1232-, 2017

50 Cameron MJ, "Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome" 81 : 8692-8706, 2007

51 Sallenave JM, "Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in COVID-19 : key therapeutic targets" 11 : 1229-, 2020

52 Monteil V, "Inhibition of SARS-CoV-2 infections in engineered human tissues using clinicalgrade soluble human ACE2" 181 : 905.e7-913.e7, 2020

53 Felgenhauer U, "Inhibition of SARS-CoV-2 by type I and type III interferons" 295 : 13958-13964, 2020

54 Bertram S, "Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts" 7 : e35876-, 2012

55 Wang M, "Inflammatory endotypes of CRSwNP and responses to COVID-19" 21 : 8-15, 2021

56 Gamage AM, "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" 16 : e1009130-, 2020

57 Zhuang MW, "Increasing host cellular receptorangiotensin-converting enzyme 2 expression by coronavirus may facilitate 2019-nCoV(or SARS-CoV-2)infection" 92 : 2693-2701, 2020

58 Hadjadj J, "Impaired type I interferon activity and inflammatory responses in severe COVID-19patients" 369 : 718-724, 2020

59 Lee JS, "Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19" 5 : eabd1554-, 2020

60 Brodin P, "Immune determinants of COVID-19 disease presentation and severity" 27 : 28-33, 2021

61 Blanco-Melo D, "Imbalanced host response to SARS-CoV-2 drives development of COVID-19" 181 : 1036-1045, 2020

62 Zhang R, "Identifying airborne transmission as the dominant route for the spread of COVID-19" 117 : 14857-14863, 2020

63 Han Y, "Identification of SARS-CoV-2 inhibitors using lung and colonic organoids" 589 : 270-275, 2021

64 Riphagen S, "Hyperinflammatory shock in children during COVID-19 pandemic" 395 : 1607-1608, 2020

65 Matheson NJ, "How does SARS-CoV-2 cause COVID-19" 369 : 510-511, 2020

66 Bost P, "Host-viral infection maps reveal signatures of severe COVID-19 patients" 181 : 1475.e12-1488.e12, 2020

67 Narasaraju T, "Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19" 173 : 323-324, 2020

68 Ortiz ME, "Heterogeneous expression of the SARS-coronavirus-2 receptor ACE2 in the human respiratory tract" 60 : 102976-, 2020

69 Aguiar JA, "Gene expression and in situ protein profiling of candidate SARS-CoV-2receptors in human airway epithelial cells and lung tissue" 56 : 2001123-, 2020

70 Drożdżal S, "FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2(COVID-19)therapy" 53 : 100719-, 2020

71 Zhang H, "Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium" 202 : 219-229, 2020

72 Yao Y, "Expression of ACE2 in airways : Implication for COVID-19 risk and disease management in patients with chronic inflammatory respiratory diseases" 50 : 1313-1324, 2020

73 Chen M, "Elevated ACE-2 expression in the olfactory neuroepithelium : implications for anosmia and upper respiratory SARS-CoV-2 entry and replication" 56 : 2001948-, 2020

74 Hur S, "Double-stranded RNA sensors and modulators in innate immunity" 37 : 349-375, 2019

75 Ming Wang, "Distinct expression of SARS‐CoV‐2 receptor ACE2 correlates with endotypes of chronic rhinosinusitis with nasal polyps" Wiley 76 (76): 789-803, 2021

76 Purkayastha A, "Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response" 27 : 869.e4-875.e4, 2020

77 Raj VS, "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC" 495 : 251-254, 2013

78 Lau SKP, "Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus : implications for pathogenesis and treatment" 94 : 2679-2690, 2013

79 Tata PR, "Dedifferentiation of committed epithelial cells into stem cells in vivo" 503 : 218-223, 2013

80 Moore JB, "Cytokine release syndrome in severe COVID-19" 368 : 473-474, 2020

81 Wrapp D, "Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation" 367 : 1260-1263, 2020

82 Vlek ALM, "Combined throat/nasal swab sampling for SARSCoV-2 is equivalent to nasopharyngeal sampling" 40 : 193-195, 2021

83 Wang D, "Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China" 323 : 1061-1069, 2020

84 Chen G, "Clinical and immunological features of severe and moderate coronavirus disease 2019" 130 : 2620-2629, 2020

85 Chua RL, "COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis" 38 : 970-979, 2020

86 Prokunina-Olsson L, "COVID-19 and emerging viral infections : the case for interferon lambda" 217 : 217-, 2020

87 Bedford J, "COVID-19 : towards controlling of a pandemic" 395 : 1015-1018, 2020

88 Hirano T, "COVID-19 : a new virus, but a familiar receptor and cytokine release syndrome" 52 : 731-733, 2020

89 Wang K, "CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells" 5 : 283-, 2020

90 Jackson DJ, "Association of respiratory allergy, asthma, and expression of the SARS-CoV-2receptor ACE2" 146 : 203.e3-206.e3, 2020

91 Fink SL, "Apoptosis, pyroptosis, and necrosis : mechanistic description of dead and dying eukaryotic cells" 73 : 1907-1916, 2005

92 Mantlo E, "Antiviral activities of type I interferons to SARS-CoV-2 infection" 179 : 104811-, 2020

93 Imai Y, "Angiotensinconverting enzyme 2 protects from severe acute lung failure" 436 : 112-116, 2005

94 Zhang H, "Angiotensin-converting enzyme 2(ACE2)as a SARSCoV-2 receptor : molecular mechanisms and potential therapeutic target" 46 : 586-590, 2020

95 Crackower MA, "Angiotensin-converting enzyme 2 is an essential regulator of heart function" 417 : 822-828, 2002

96 Li W, "Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus" 426 : 450-454, 2003

97 Huang F, "Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients" 5 : 3595-, 2014

98 Lamers MM, "An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells" 2020

99 Xie X, "An infectious cDNA clone of SARS-CoV-2" 27 : 841-848, 2020

100 Saheb Sharif-Askari N, "Airways expression of SARS-CoV-2 receptor, ACE2, and TMPRSS2 is lower in children than adults and increases with smoking and COPD" 18 : 1-6, 2020

101 Bajaj V, "Aging, immunity, and COVID-19 : how age influences the host immune response to coronavirus infections" 11 : 571416-, 2021

102 Inde Z, "Agedependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19disease severity"

103 Schouten LR, "Age-dependent differences in pulmonary host responses in ARDS : a prospective observational cohort study" 9 : 55-, 2019

104 Lee IT, "ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs" 11 : 5453-, 2020

105 Leung JM, "ACE-2expression in the small airway epithelia of smokers and COPD patients : implications for COVID-19" 55 : 55-, 2020

106 Zhou P, "A pneumonia outbreak associated with a new coronavirus of probable bat origin" 579 : 270-273, 2020

107 Khan A, "A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome" 21 : 234-, 2017

108 Zhu N, "A novel coronavirus from patients with pneumonia in China, 2019" 382 : 727-733, 2020

109 Donoghue M, "A novel angiotensin-converting enzyme-related carboxypeptidase(ACE2)converts angiotensin I to angiotensin 1-9" 87 : E1-E9, 2000

110 Wu F, "A new coronavirus associated with human respiratory disease in China" 579 : 265-269, 2020

111 Kuba K, "A crucial role of angiotensin converting enzyme 2(ACE2)in SARS coronavirus-induced lung injury" 11 : 875-879, 2005

112 Gordon DE, "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing" 583 : 459-468, 2020