TMPRSS2 is dispensable for lethal SARS-CoV-2 BA.5 infection in humanized hACE2 golden hamsters.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) can specifically bind to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface via the corresponding spike (S) protein, facilitating the entry of the virus. ACE2 is highly expressed in alveolar type II cells, respiratory epithelial cells, and various other tissues, which provides favorable conditions for the transmission of SARS-CoV-2. TMPRSS2, a transmembrane serine protease widely distributed in the respiratory tract and digestive tract, cleaves the receptor-binding domain (RBD) and S1/S2 subunit of the SARS-CoV-2 spike protein. The protein cleavage activates the virus and enhances its binding to ACE2. This study reported for the first time that Tmprss2 deficiency reduces susceptibility to SARS-CoV-2 in golden hamsters. Infection experiments were conducted with three SARS-CoV-2 variants (Beta, BA.5, and XBB). The findings revealed that compared to the wild-type control, TMPRSS2 knockout in hamsters resulted in lower viral titers in the lungs and reduced pathological damage. Our results showed that Tmprss2 KO;H11-K18-hACE2 hamsters succumbed to infection with SARS-CoV-2 (BA.5 strain) by day 5 post-inoculation, similar to H11-K18-hACE2 hamsters. These findings indicated that SARS-CoV-2-induced mortality in humanized hACE2 hamsters occurs independently of TMPRSS2.