Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort

Carapito, Raphaël; Li, Richard; Helms, Julie; Carapito, Christine; Gujja, Sharvari; Rolli, Véronique; Guimaraes, Raony; Malagon-Lopez, Jose; Spinnhirny, Perrine; Lederle, Alexandre; Mohseninia, Razieh; Hirschler, Aurélie; Muller, Leslie; Bastard, Paul; Gervais, Adrian; Zhang, Qian; Danion, François; Ruch, Yvon; Schenck, Maleka; Collange, Olivier; Chamaraux-Tran, Thiên-Nga; Molitor, Anne; Pichot, Angélique; Bernard, Alice; Tahar, Ouria; Bibi-Triki, Sabrina; Wu, Hai‐Chen; Paul, Nicodéme; Mayeur, Sylvain; Larnicol, Annabel; Laumond, Géraldine; Frappier, Julia; Schmidt, Sylvie; Hanauer, Antoine; Macquin, Cécile; Stemmelen, Tristan; Simons, Michael; Mariette, Xavier; Hermine, Olivier; Fafi‐Kremer, Samira; Goichot, B.; Drénou, Bernard; Kuteifan, Khaldoun; Pottecher, Julien; Mertès, Paul-Michel; Kailasan, Shweta; Aman, M. Javad; Pin, Elisa; Nilsson, Peter; Thomas, Anne; Viari, Alain; Sanlaville, Damien; Schneider, Francis; Sibilia, Jean; Tharaux, Pierre‐Louis; Casanova, Jean‐Laurent; Hansmann, Yves; Lidar, Daniel A.; Radosavljevic, Mirjana; Gulcher, Jeffrey R.; Meziani, Ferhat; Moog, Christiane; Chittenden, Thomas; Bahram, Seiamak

doi:10.1126/scitranslmed.abj7521

Cited by 101 publications

(75 citation statements)

References 102 publications

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“…ADAM10 and ADAM17 thus both play crucial but distinct roles in SARS-CoV-2 infection. It has recently been reported that ADAM9 inhibition decreases SARS-CoV-2 infection in vitro [62]. Although the involvement of ADAM9 in viral entry is not clear, the results suggest that a group of metalloproteinases cooperate in the metalloproteinase pathway.…”

Section: Discussionmentioning

confidence: 80%

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Yamamoto

Gohda

Kobayashi

et al. 2021

Preprint

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The ongoing global vaccination program to prevent SARS-CoV-2 infection, the causative agent of COVID-19, has had significant success. However, recently virus variants have emerged that can evade the immunity in a host achieved through vaccination. Consequently, new therapeutic agents that can efficiently prevent infection from these new variants, and hence COVID-19 spread are urgently required. To achieve this, extensive characterization of virus-host cell interactions to identify effective therapeutic targets is warranted. Here, we report a cell surface entry pathway of SARS-CoV-2 that exists in a cell type-dependent manner is TMPRSS2-independent but sensitive to various broad-spectrum metalloproteinase inhibitors such as marimastat and prinomastat. Experiments with selective metalloproteinase inhibitors and gene-specific siRNAs revealed that a disintegrin and metalloproteinase 10 (ADAM10) is partially involved in the metalloproteinase pathway. Consistent with our finding that the pathway is unique to SARS-CoV-2 among highly pathogenic human coronaviruses, both the furin cleavage motif in the S1/S2 boundary and the S2 domain of SARS-CoV-2 spike protein are essential for metalloproteinase-dependent entry. In contrast, the two elements of SARS-CoV-2 independently contributed to TMPRSS2-dependent S2 priming. The metalloproteinase pathway is involved in SARS-CoV-2-induced syncytia formation and cytopathicity, leading us to theorize that it is also involved in the rapid spread of SARS-CoV-2 and the pathogenesis of COVID-19. Thus, targeting the metalloproteinase pathway in addition to the TMPRSS2 and endosome pathways could be an effective strategy by which to cure COVID-19 in the future.

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Section: Discussionmentioning

confidence: 80%

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Yamamoto

Gohda

Kobayashi

et al. 2021

Preprint

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“…These auto-Abs were mostly found in men (95%), and half the patients carrying them were over the age of 65 yr ( Bastard et al, 2020b ). These findings were subsequently widely replicated in independent cohorts ( Abers et al, 2021 ; Acosta-Ampudia et al, 2021 ; Carapito et al, 2022 ; Chang et al, 2021 ; Chauvineau-Grenier et al, 2022 ; Goncalves et al, 2021 ; Koning et al, 2021 ; Raadsen et al, 2022 ; Solanich et al, 2021 ; Troya et al, 2021 ; van der Wijst et al, 2021 ; Vazquez et al, 2021 ; Wang et al, 2021 ; Zhang et al, 2022 ; Ziegler et al, 2021 ). Consistently, patients with APS-1 and preexisting anti–type I IFN auto-Abs were found to be at very high risk of severe disease upon SARS-CoV-2 infection ( Bastard et al, 2020b ; Beccuti et al, 2020 ; Carpino et al, 2021 ).…”

Section: Neutralizing Auto-abs Against Type I Ifns Underlie Severe Or...mentioning

confidence: 72%

Human autoantibodies underlying infectious diseases

Puel

Bastard

Bustamante

et al. 2022

Journal of Experimental Medicine

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The vast interindividual clinical variability observed in any microbial infection—ranging from silent infection to lethal disease—is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.

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“…S2’ priming causes membrane fusion between the viral particle and the plasma or endosomal membrane through interaction between the fusion peptide region and the cellular membrane, resulting in the release of viral RNA into the cytoplasm and its replication. We and others recently showed that host metalloproteinases are also involved in cell surface entry, independent of transmembrane protease, serine 2 (TMPRSS2) [21-23]. These results suggest that metalloproteinases act as the third host proteases for SARS-CoV-2 entry.…”

Section: Introductionmentioning

confidence: 88%

SARS-CoV-2 Omicron spike H655Y mutation is responsible for enhancement of the endosomal entry pathway and reduction of cell surface entry pathways

Yamamoto

Tomita

Hirayama

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant reportedly displays decreased usage of the cell surface entry pathway mediated by the host transmembrane protease, serine 2 (TMPRSS2) and increased usage of the endosomal entry pathway mediated by cathepsin B/L. These differences result in different cell tropisms and low fusogenicity from other SARS-CoV-2 variants. Recent studies have revealed that host metalloproteases are also involved in cell surface entry and fusogenic activity of SARS-CoV-2, independent of TMPRSS2. However, the involvement of metalloproteinase-mediated cell entry and fusogenicity in Omicron infections has not been investigated. Here, we report that Omicron infection is less sensitive to the metalloproteinase inhibitor marimastat, like the TMPRSS2 inhibitor nafamostat, and is more sensitive to the cathepsin B/L inhibitor E-64d than infections with wild-type SARS-CoV-2 and other variants. The findings indicate that Omicron preferentially utilizes the endosomal pathway rather than cell surface pathways for entry. Moreover, the Omicron variant also displays poor syncytia formation mediated by metalloproteinases, even when the S cleavage status mediated by fusion-like proteases is unchanged. Intriguingly, the pseudovirus assay showed that a single mutation, H655Y, of the Omicron spike (S) is responsible for the preferential entry pathway usage without affecting the S cleavage status. These findings suggest that the Omicron variant has altered entry properties and fusogenicity, probably through the H655Y mutation in its S protein, leading to modulations of tissue and cell tropism, and reduced pathogenicity.Author summaryRecent studies have suggested that the SARS-CoV-2 Omicron variant displays altered cell tropism and fusogenicity, in addition to immune escape. However, comprehensive analyses of the usage of viral entry pathways in Omicron variant have not been performed. Here, we used protease inhibitors to block each viral entry pathway mediated by the three host proteases (cathepsin B/L, TMPRSS2, and metalloproteinases) in various cell types. The results clearly indicated that Omicron exhibits enhanced cathepsin B/L-dependent endosome entry and reduced metalloproteinase-dependent and TMPRSS2-dependent cell surface entry. Furthermore, the H655Y mutation of Omicron S determines the relative usage of the three entry pathways without affecting S cleavage by the host furin-like proteases. Comparative data among SARS-CoV-2 variants, including Omicron, may clarify the biological and pathological phenotypes of Omicron but increase the understanding of disease progression in infections with other SARS-CoV-2 variants.

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Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort

Cited by 101 publications

References 102 publications

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Human autoantibodies underlying infectious diseases

SARS-CoV-2 Omicron spike H655Y mutation is responsible for enhancement of the endosomal entry pathway and reduction of cell surface entry pathways

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