iScience (Nov 2022)
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,
- Patrick M. Giguère,
- Samira Mubareka,
- Andrés Finzi,
- Gregory A. Dekaban,
- Jimmy D. Dikeakos,
- Marceline Côté
Affiliations
- Mehdi Benlarbi
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Geneviève Laroche
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Corby Fink
- Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry Western University, London, ON N6A 5C1, Canada; Molecular Medicine Research Laboratories, Robarts Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada
- Kathy Fu
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Rory P. Mulloy
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Alexandra Phan
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Ardeshir Ariana
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Corina M. Stewart
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Jérémie Prévost
- Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
- Guillaume Beaudoin-Bussières
- Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
- Redaet Daniel
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Yuxia Bo
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Omar El Ferri
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Julien Yockell-Lelièvre
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; The Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- William L. Stanford
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; The Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Patrick M. Giguère
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Samira Mubareka
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Andrés Finzi
- Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
- Gregory A. Dekaban
- Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry Western University, London, ON N6A 5C1, Canada; Molecular Medicine Research Laboratories, Robarts Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada
- Jimmy D. Dikeakos
- Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry Western University, London, ON N6A 5C1, Canada; Molecular Medicine Research Laboratories, Robarts Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada
- Marceline Côté
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 11
p. 105316
Abstract
Summary: 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.
