Identification of a SARS-CoV-2 host metalloproteinase-dependent entry pathway differentially used by SARS-CoV-2 and variants of concern Alpha, Delta, and Omicron
ABSTRACT To infect cells, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) via its spike glycoprotein (S), delivering its genome upon S-mediated membrane fusion. SARS-CoV-2 uses two distinct entry pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In investigating serine protease-independent cell-cell fusion, we found that the matrix metalloproteinases (MMPs), MMP2/9, can activate SARS-CoV-2 S fusion activity, but not that of SARS-CoV-1. Importantly, metalloproteinase activation of SARS-CoV-2 S represents a third entry pathway in cells expressing high MMP levels. This route of entry required cleavage at the S1/S2 junction in viral producer cells and differential processing of variants of concern S dictated its usage. In addition, metalloproteinase inhibitors reduced replicative Alpha infection and abrogated syncytia formation. Finally, we found that the Omicron S exhibit reduced metalloproteinase-dependent fusion and viral entry. Taken together, we identified a MMP2/9-dependent mode of activation of SARS-CoV-2 S. As MMP2/9 are released during inflammation and severe COVID-19, they may play important roles in SARS-CoV-2 S-mediated cytopathic effects, tropism, and disease outcome..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 29. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Benlarbi, Mehdi [VerfasserIn] |
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| doi: |
10.1101/2022.02.19.481107 |
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| PPN (Katalog-ID): |
XBI035305835 |
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| 245 | 1 | 0 | |a Identification of a SARS-CoV-2 host metalloproteinase-dependent entry pathway differentially used by SARS-CoV-2 and variants of concern Alpha, Delta, and Omicron |
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| 520 | |a ABSTRACT To infect cells, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) via its spike glycoprotein (S), delivering its genome upon S-mediated membrane fusion. SARS-CoV-2 uses two distinct entry pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In investigating serine protease-independent cell-cell fusion, we found that the matrix metalloproteinases (MMPs), MMP2/9, can activate SARS-CoV-2 S fusion activity, but not that of SARS-CoV-1. Importantly, metalloproteinase activation of SARS-CoV-2 S represents a third entry pathway in cells expressing high MMP levels. This route of entry required cleavage at the S1/S2 junction in viral producer cells and differential processing of variants of concern S dictated its usage. In addition, metalloproteinase inhibitors reduced replicative Alpha infection and abrogated syncytia formation. Finally, we found that the Omicron S exhibit reduced metalloproteinase-dependent fusion and viral entry. Taken together, we identified a MMP2/9-dependent mode of activation of SARS-CoV-2 S. As MMP2/9 are released during inflammation and severe COVID-19, they may play important roles in SARS-CoV-2 S-mediated cytopathic effects, tropism, and disease outcome. | ||
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| 700 | 1 | |a Fu, Kathy |e verfasserin |4 aut | |
| 700 | 1 | |a Mulloy, Rory P. |e verfasserin |4 aut | |
| 700 | 1 | |a Phan, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Ariana, Ardeshir |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Corina M. |e verfasserin |4 aut | |
| 700 | 1 | |a Prévost, Jérémie |e verfasserin |4 aut | |
| 700 | 1 | |a Beaudoin-Bussières, Guillaume |e verfasserin |4 aut | |
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| 700 | 1 | |a Bo, Yuxia |e verfasserin |4 aut | |
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| 700 | 1 | |a Giguère, Patrick M. |e verfasserin |4 aut | |
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| 700 | 1 | |a Dekaban, Gregory A. |e verfasserin |4 aut | |
| 700 | 1 | |a Dikeakos, Jimmy D. |e verfasserin |4 aut | |
| 700 | 1 | |a Côté, Marceline |e verfasserin |4 aut | |
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