The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.
- Jocher, G.
- Grass, V.
- Tschirner, S. K.
- Riepler, L.
- Breimann, S.
- Kaya, T.
- Oelsner, M.
- Hamad, M. S.
- Hofmann, L. I.
- Blobel, C. P.
- Schmidt-Weber, C. B.
- Gokce, O.
- Jakwerth, C. A.
- Trimpert, J.
- Kimpel, J.
- Pichlmair, A.
- Lichtenthaler, S. F.
Keywords
- A549
- Dpc-333
- apratastat
- ectodomain shedding
- syncytia formation
