Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron
Mehdi Benlarbi, Geneviève Laroche, Corby Fink, Kathy Fu, Rory P. Mulloy, Alexandra Phan, Ardeshir Ariana, Corina M. Stewart, Jérémie Prévost, Guillaume Beaudoin-Bussières, Redaet Daniel, Yuxia Bo, Omar El Ferri, Julien Yockell‐Lelièvre, William L. Stanford, Philippe Giguère, Samira Mubareka, Andrés Finzi, Gregory A. Dekaban, Jimmy D. Dikeakos, Marceline Côté
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell fusion and TMPRSS2- and cathepsin-independent viral entry in cells expressing high MMP levels. MMP-dependent viral entry required cleavage at the S1/S2 junction in viral producer cells, and differential processing of variants of concern S dictated its usage; the efficiently processed Delta S preferred metalloproteinase-dependent entry when available, and less processed Omicron S was unable to us metalloproteinases for entry. As MMP-2/9 are released during inflammation, they may play roles in S-mediated cytopathic effects, tropism, and disease outcome.