Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers

Tsuguhisa Nakayama; Ivan T Lee; Sizun Jiang; Matthias S Matter; Carol H Yan; Jonathan B Overdevest; Chien-Ting Wu; Yury Goltsev; Liang-Chun Shih; Chun-Kang Liao; Bokai Zhu; Yunhao Bai; Peter Lidsky; Yinghong Xiao; David Zarabanda; Angela Yang; Meena Easwaran; Christian M Schürch; Pauline Chu; Han Chen; Anna K Stalder; David R McIlwain; Nicole A Borchard; Phillip A Gall; Sachi S Dholakia; Wei Le; Le Xu; Chih-Jaan Tai; Te-Huei Yeh; Elizabeth Erickson-Direnzo; Jason M Duran; Kirsten D Mertz; Peter H Hwang; Jasmin D Haslbauer; Peter K Jackson; Thomas Menter; Raul Andino; Peter D Canoll; Adam S DeConde; Zara M Patel; Alexandar Tzankov; Garry P Nolan; Jayakar V Nayak

doi:10.1016/j.xcrm.2021.100421

Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers

Cell Rep Med. 2021 Oct 19;2(10):100421. doi: 10.1016/j.xcrm.2021.100421. Epub 2021 Sep 28.

Authors

Tsuguhisa Nakayama^{1

2}, Ivan T Lee^{1

3

4}, Sizun Jiang^{4

5}, Matthias S Matter⁶, Carol H Yan⁷, Jonathan B Overdevest⁸, Chien-Ting Wu⁹, Yury Goltsev⁴, Liang-Chun Shih^{10

11

12}, Chun-Kang Liao¹³, Bokai Zhu⁴, Yunhao Bai⁴, Peter Lidsky¹⁴, Yinghong Xiao¹⁴, David Zarabanda¹, Angela Yang¹, Meena Easwaran¹, Christian M Schürch⁴, Pauline Chu⁴, Han Chen⁴, Anna K Stalder⁶, David R McIlwain⁴, Nicole A Borchard¹, Phillip A Gall¹, Sachi S Dholakia¹, Wei Le¹, Le Xu¹⁵, Chih-Jaan Tai^{10

16}, Te-Huei Yeh^{13

17}, Elizabeth Erickson-Direnzo¹, Jason M Duran¹⁸, Kirsten D Mertz¹⁹, Peter H Hwang¹, Jasmin D Haslbauer⁶, Peter K Jackson⁹, Thomas Menter⁶, Raul Andino¹⁴, Peter D Canoll²⁰, Adam S DeConde⁷, Zara M Patel¹, Alexandar Tzankov⁶, Garry P Nolan⁴, Jayakar V Nayak^{1

21}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, 801 Welch Road, Stanford, CA, USA.
² Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
³ Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁶ Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷ Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of California San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁸ Department of Otolaryngology-Head and Neck Surgery, Columbia University School of Medicine, New York, NY, USA.
⁹ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan.
¹¹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
¹² Terry Fox Cancer Research Laboratory, Translational Medicine Center, China Medical University Hospital, Taichung, Taiwan.
¹³ Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁴ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Department of Pediatrics, University of California San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA.
¹⁶ School of Medicine, China Medical University, Taichung, Taiwan.
¹⁷ Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁸ Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA.
¹⁹ Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.
²⁰ Department of Pathology and Cell Biology, Columbia University Medical Center, Irving Cancer Research Center, New York, NY, USA.
²¹ Department of Otolaryngology - Head and Neck Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.

Abstract

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers.

Keywords: ACE2; COVID-19; IFN-β1; SARS-CoV-2; TMPRSS2; ciliated epithelial cell; nasal cavity; smoking; trachea; upper airway.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Aged, 80 and over
Angiotensin-Converting Enzyme 2 / genetics*
COVID-19 / genetics
COVID-19 / metabolism
COVID-19 / transmission*
Female
Gene Expression Regulation
Humans
Male
Middle Aged
Nasal Cavity / metabolism
Respiratory Mucosa / metabolism*
SARS-CoV-2 / physiology
Serine Endopeptidases / genetics*
Smokers*
Trachea / metabolism
Viral Tropism*

Substances

ACE2 protein, human
Angiotensin-Converting Enzyme 2
Serine Endopeptidases
TMPRSS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding