Since the beginning of 2020, SARS-CoV-2, the virus responsible for COVID-19, has infected more than 179 million people worldwide and killed more than 3.8 million. Apart from vaccines, the most effective strategy to limit the spread of the virus is to target the early stages of infection and to prevent the virus from entering cells. To this end, it is essential to understand how the virus penetrates the cells.

Researchers from the University Heidelberg in close collaboration with IVPC has shown that SARS-CoV-2 infect cells rapidly (10 min) when they express the surface protease TMPRSS2, which SARS-CoV-2 exclusively uses for penetration in these cells. TMPRSS2 was notably found in the lung and intestine, where the virus is most strongly detected. When the protease TMPRSS2 is absent, the virus takes another route, slower (about 50 min) via the endolysosomal pathway. In this scenario, SARS-CoV-2 requires an acidic environment, critical for the functioning of endolysosomal proteases that are necessary for the virus activation. These results show that, with the ability to utilize diverse cell entry routes, SARS-CoV-2 has likely found a way to expand its number of target tissues and organs, which certainly contributes to the broad tropism of the virus in vivo and its spread. This study also provides explanations why some of the treatments that target only one of the two pathways are ineffective.

This study lays the basis for the development of antiviral strategies more effective that simultaneously target both virus entry pathways. The results are published on June 23^rd 2021 in the EMBO J.