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TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells.
Koch, Jana; Uckeley, Zina M; Doldan, Patricio; Stanifer, Megan; Boulant, Steeve; Lozach, Pierre-Yves.
  • Koch J; Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany.
  • Uckeley ZM; CellNetworks - Cluster of Excellence, Heidelberg, Germany.
  • Doldan P; Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
  • Stanifer M; Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, Heidelberg, Germany.
  • Boulant S; CellNetworks - Cluster of Excellence, Heidelberg, Germany.
  • Lozach PY; Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
EMBO J ; 40(16): e107821, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1280957
ABSTRACT
SARS-CoV-2 is a newly emerged coronavirus that caused the global COVID-19 outbreak in early 2020. COVID-19 is primarily associated with lung injury, but many other clinical symptoms such as loss of smell and taste demonstrated broad tissue tropism of the virus. Early SARS-CoV-2-host cell interactions and entry mechanisms remain poorly understood. Investigating SARS-CoV-2 infection in tissue culture, we found that the protease TMPRSS2 determines the entry pathway used by the virus. In the presence of TMPRSS2, the proteolytic process of SARS-CoV-2 was completed at the plasma membrane, and the virus rapidly entered the cells within 10 min in a pH-independent manner. When target cells lacked TMPRSS2 expression, the virus was endocytosed and sorted into endolysosomes, from which SARS-CoV-2 entered the cytosol via acid-activated cathepsin L protease 40-60 min post-infection. Overexpression of TMPRSS2 in non-TMPRSS2 expressing cells abolished the dependence of infection on the cathepsin L pathway and restored sensitivity to the TMPRSS2 inhibitors. Together, our results indicate that SARS-CoV-2 infects cells through distinct, mutually exclusive entry routes and highlight the importance of TMPRSS2 for SARS-CoV-2 sorting into either pathway.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Serine Endopeptidases / Cathepsin L / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: EMBO J Year: 2021 Document Type: Article Affiliation country: Embj.2021107821

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Serine Endopeptidases / Cathepsin L / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: EMBO J Year: 2021 Document Type: Article Affiliation country: Embj.2021107821