tetano
Editor, Senior Moderator
EMBO J
. 2021 Jun 23;e107821.
doi: 10.15252/embj.2021107821. Online ahead of print.
TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells
Jana Koch[SUP] 1 2 3 [/SUP], Zina M Uckeley[SUP] 1 2 3 [/SUP], Patricio Doldan[SUP] 1 3 [/SUP], Megan Stanifer[SUP] 1 4 [/SUP], Steeve Boulant[SUP] 1 3 5 [/SUP], Pierre-Yves Lozach[SUP] 1 2 3 6 [/SUP]
Affiliations
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.
Keywords: COVID-19; Coronavirus; SARS-CoV-2; protease; virus entry.
. 2021 Jun 23;e107821.
doi: 10.15252/embj.2021107821. Online ahead of print.
TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells
Jana Koch[SUP] 1 2 3 [/SUP], Zina M Uckeley[SUP] 1 2 3 [/SUP], Patricio Doldan[SUP] 1 3 [/SUP], Megan Stanifer[SUP] 1 4 [/SUP], Steeve Boulant[SUP] 1 3 5 [/SUP], Pierre-Yves Lozach[SUP] 1 2 3 6 [/SUP]
Affiliations
- PMID: 34159616
- DOI: 10.15252/embj.2021107821
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.
Keywords: COVID-19; Coronavirus; SARS-CoV-2; protease; virus entry.