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

doi:10.1016/j.isci.2022.105316

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

iScience. 2022 Nov 18;25(11):105316. doi: 10.1016/j.isci.2022.105316. Epub 2022 Oct 10.

Authors

Mehdi Benlarbi^{1

2

3}, Geneviève Laroche^{1

2

3}, Corby Fink^{4

5}, Kathy Fu^{1

2

3}, Rory P Mulloy^{1

2

3}, Alexandra Phan^{1

2

3}, Ardeshir Ariana^{1

2

3}, Corina M Stewart^{1

2

3}, Jérémie Prévost^{6

7}, Guillaume Beaudoin-Bussières^{6

7}, Redaet Daniel^{1

2

3}, Yuxia Bo^{1

2

3}, Omar El Ferri^{1

2

3}, Julien Yockell-Lelièvre^{1

2

8

9}, William L Stanford^{1

2

8

9}, Patrick M Giguère¹, Samira Mubareka^{10

11}, Andrés Finzi^{6

7}, Gregory A Dekaban^{4

5}, Jimmy D Dikeakos^{4

5}, Marceline Côté^{1

2

3}

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
² Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
³ Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁴ Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry Western University, London, ON N6A 5C1, Canada.
⁵ Molecular Medicine Research Laboratories, Robarts Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada.
⁶ Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada.
⁷ Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁸ The Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
⁹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
¹⁰ Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.

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.

Keywords: Biological sciences; microbiology; molecular biology; virology.