TY  - JOUR
AU  - Koch, Jana
AU  - Uckeley, Zina M
AU  - Doldan, Patricio
AU  - Stanifer, Megan
AU  - Boulant, Steeve
AU  - Lozach, Pierre-Yves
TI  - TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells.
JO  - The EMBO journal
VL  - 40
IS  - 16
SN  - 1460-2075
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DKFZ-2021-01608
SP  - e107821
PY  - 2021
N1  - 2021 Aug 16;40(16):e107821
AB  - 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.
KW  - COVID-19 (Other)
KW  - Coronavirus (Other)
KW  - SARS-CoV-2 (Other)
KW  - protease (Other)
KW  - virus entry (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34159616
DO  - DOI:10.15252/embj.2021107821
UR  - https://inrepo02.dkfz.de/record/169874
ER  -