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.
【저자키워드】 COVID-19, SARS-CoV-2, coronavirus, protease, Virus entry., 【초록키워드】 TMPRSS2, SARS-COV-2 infection, Infection, Lung injury, protease, virus, sensitivity, Culture, COVID-19 outbreak, virus entry, pathway, Entry mechanism, Taste, tissue culture, target cells, tissue tropism, cathepsin L, target cell, TMPRSS2 inhibitors, Loss of Smell, Post-infection, cell interaction, dependence, tissue, clinical symptom, TMPRSS2 expression, loss of smell and taste, cathepsin L pathway, entry pathway, plasma membrane, protease TMPRSS2, overexpression, cytosol, infect, Endolysosomes, Cell, entry mechanisms, highlight, caused, determine, demonstrated, restored, expressing, endocytosed, entry route, proteolytic, 【제목키워드】 host cell, infect,