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

Benlarbi, Mehdi; Laroche, Geneviève; Fink, Corby; Fu, Kathy; Mulloy, Rory P.; Phan, Alexandra; Ariana, Ardeshir; Stewart, Corina M; Prévost, Jérémie; Beaudoin-Bussières, Guillaume; Daniel, R. Neill; Bo, Yuxia; Ferri, Omar El; Yockell‐Lelièvre, Julien; Stanford, William; Giguère, Patrick M.; Mubareka, Samira; Finzi, Andrés; Dekaban, Gregory A.; Dikeakos, Jimmy D.; Côté, Marceline

doi:10.1016/j.isci.2022.105316

Cited by 20 publications

(12 citation statements)

References 95 publications

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“…14b), suggesting that MT1-MMP-dependent control of viral entry is mainly mediated through ACE2 shedding. Even though MMP cleavage-fusion activation of spike proteins has been demonstrated to promote SARS-CoV-2 entry 61,62 , our study suggests that other MMPs, but not MT1-MMP, may be involved in this cleavage process. The differential roles of different MMPs in SARS-CoV-2 infection certainly warrant further investigation in the future.…”

Section: Discussionmentioning

confidence: 60%

Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.

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Section: Discussionmentioning

confidence: 60%

Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

et al. 2022

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“…The next day, cells were transfected with the appropriate spike plasmid (Wuhan-Hu-1: BEI NR-52310; Delta: Addgene no. 185593, a gift from Marceline Côté, [31]; Omicron: Addgene no. 185452, a gift from Marceline Côté, [32]) using the calcium-phosphate profection mammalian transfection system (Promega).…”

Section: Methodsmentioning

confidence: 99%

Beluga whale and bottlenose dolphin ACE2 proteins allow cell entry mediated by spike protein from three variants of SARS-CoV-2

Stone,

Unal,

Romano

et al. 2023

Biol. Lett.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses infect numerous non-human species. Spillover of SARS-CoV-2 into novel animal reservoirs may present a danger to host individuals of these species, particularly worrisome in populations already endangered or threatened by extinction. In addition, emergence in new reservoirs could pose spillback threats to humans, especially in the form of virus variants that further mutate when infecting other animal hosts. Previous work suggests beluga whales ( Delphinapterus leucas ) and bottlenose dolphins ( Tursiops truncatus ) may be at risk owing to their formation of social groups, contact with humans, exposure to contaminated wastewater, and structure of their angiotensin-converting enzyme 2 (ACE2) proteins, which SARS-CoV-2 uses as a cellular receptor. We examined marine-mammal susceptibility to virus infection by challenging 293T cells expressing beluga or dolphin ACE2 with pseudovirions bearing the SARS-CoV-2 spike protein. Beluga and dolphin ACE2 were sufficient to allow cell entry by an early pandemic isolate (Wuhan-Hu-1) and two evolved variants (Delta B.1.617.2 and Omicron BA.1 strains). We conclude that SARS-CoV-2 poses a potential threat to marine mammal reservoirs that should be considered in surveillance efforts.

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“…An early study showed that MMP inhibitors had no effect on spike S1/S2 cleavage [ 12 ], suggesting that MMPs may play a role during the activation of the spikes. However, Omicron subvariants not only reduced TMPRSS2 usage, but also reduced the metalloproteinases usage at the plasma membrane, since these inhibitors did not block Omicron BA.1 and BA.2 entry via endocytosis [ 142 ]. Certain proteases can be contributed by infiltrating innate immune cells, such as the neutrophil elastase (ELANE), which specifically cleaves the threonine 795 residue of the SARS-CoV spike upstream of the S2′ (R797) cleavage site [ 143 ].…”

Section: Spike Proteolytic Activation and Utilization Of Host Proteasesmentioning

confidence: 99%

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

et al. 2023

Viruses

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The constantly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) fuel the worldwide coronavirus disease (COVID-19) pandemic. The spike protein is essential for the SARS-CoV-2 viral entry and thus has been extensively targeted by therapeutic antibodies. However, mutations along the spike in SARS-CoV-2 VOC and Omicron subvariants have caused more rapid spread and strong antigenic drifts, rendering most of the current antibodies ineffective. Hence, understanding and targeting the molecular mechanism of spike activation is of great interest in curbing the spread and development of new therapeutic approaches. In this review, we summarize the conserved features of spike-mediated viral entry in various SARS-CoV-2 VOC and highlight the converging proteolytic processes involved in priming and activating the spike. We also summarize the roles of innate immune factors in preventing spike-driven membrane fusion and provide outlines for the identification of novel therapeutics against coronavirus infections.

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

Cited by 20 publications

References 95 publications

Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

Beluga whale and bottlenose dolphin ACE2 proteins allow cell entry mediated by spike protein from three variants of SARS-CoV-2

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

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