Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways

Nat Commun. 2022 Oct 15;13(1):6100. doi: 10.1038/s41467-022-33911-8.


In cultured cells, SARS-CoV-2 infects cells via multiple pathways using different host proteases. Recent studies have shown that the furin and TMPRSS2 (furin/TMPRSS2)-dependent pathway plays a minor role in infection of the Omicron variant. Here, we confirm that Omicron uses the furin/TMPRSS2-dependent pathway inefficiently and enters cells mainly using the cathepsin-dependent endocytosis pathway in TMPRSS2-expressing VeroE6/TMPRSS2 and Calu-3 cells. This is the case despite efficient cleavage of the spike protein of Omicron. However, in the airways of TMPRSS2-knockout mice, Omicron infection is significantly reduced. We furthermore show that propagation of the mouse-adapted SARS-CoV-2 QHmusX strain and human clinical isolates of Beta and Gamma is reduced in TMPRSS2-knockout mice. Therefore, the Omicron variant isn't an exception in using TMPRSS2 in vivo, and analysis with TMPRSS2-knockout mice is important when evaluating SARS-CoV-2 variants. In conclusion, this study shows that TMPRSS2 is critically important for SARS-CoV-2 infection of murine airways, including the Omicron variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19*
  • Cathepsins
  • Furin / genetics
  • Furin / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Peptide Hydrolases
  • SARS-CoV-2*
  • Serine Endopeptidases / genetics
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Virus Internalization


  • Cathepsins
  • Furin
  • Peptide Hydrolases
  • Serine Endopeptidases
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • TMPRSS2 protein, human
  • TMPRSS2 protein, mouse

Supplementary concepts

  • SARS-CoV-2 variants