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 ChenAnna 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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Article number100421
JournalCell Reports Medicine
Issue number10
StatePublished - Oct 19 2021
Externally publishedYes


  • ACE2
  • COVID-19
  • IFN-β1
  • SARS-CoV-2
  • ciliated epithelial cell
  • nasal cavity
  • smoking
  • trachea
  • upper airway

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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