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.


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*


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