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  • Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron.

Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron.

iScience (2022-10-19)
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, Patrick M 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-HIV-1 P24 antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Fetal Bovine Serum, USA origin, sterile-filtered, suitable for cell culture, suitable for hybridoma
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E-64 Protease Inhibitor, The E-64 Protease Inhibitor, also referenced under CAS 66701-25-5, controls the biological activity of E-64 Protease. This small molecule/inhibitor is primarily used for Protease Inhibitors applications.
Sigma-Aldrich
MMP-2/MMP-9 Inhibitor II, The MMP-2/MMP-9 Inhibitor II, also referenced under CAS 193807-60-2, controls the biological activity of MMP-2/MMP-9. This small molecule/inhibitor is primarily used for Protease Inhibitors applications.