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ADAM10 and ADAM17 promote SARS‐CoV‐2 cell entry and spike protein‐mediated lung cell fusion

Year: 2022
Type: article
Abstract: The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.
Source: EMBO Reports
DOI: 10.15252/embr.202154305
Authors: Georg Jocher, Vincent Grass, Sarah K Tschirner, Lydia Riepler, Stephan Breimann, Tuğberk Kaya, Madlen Oelsner, M Sabri Hamad, Laura I Hofmann, Carl P Blobel, Carsten B Schmidt‐Weber, Ozgun Gokce, Constanze A Jakwerth, Jakob Trimpert, Janine Kimpel, Andreas Pichlmair, Stefan F Lichtenthaler
Institutions: German Center for Neurodegenerative Diseases, TUM Klinikum, Technical University of Munich, Innsbruck Medical University, Universität Innsbruck, LMU Klinikum, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Helmholtz Munich, German Center for Lung Research, Hospital for Special Surgery, Weill Cornell Medicine, Munich Cluster for Systems Neurology, Freie Universität Berlin, German Center for Infection Research
Language: English
Field: Medicine
Open Access status: hybrid
Estimated APC paid: $6,100
Funders: EU Joint Programme – Neurodegenerative Disease Research, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Bayerisches Staatsministerium für Bildung und Kultus, Wissenschaft und Kunst, Friedrich Naumann Stiftung, H2020 European Research Council
Awards: G1038538187, G1789099517, G2059870244, G2465168778, G2588154941, G3340888510, G3726397627, G3764482812, EXC 2145: Munich Cluster for Systems Neurology (SyNergy), G4039624579, Protein Dynamics in Antiviral Processes, ESCAPE - Angriffspunkte der Invasionsstrategie von SARS-CoV-2 in bronchialen Epithelzellen - Teilvorhaben A, Technische Universität München, Mechanismen der epithelialen Virusantwort, G626764306, G6323578953, G64039306, G6793961086, G7288349169, G8664836770
OpenAlex ID: W4229366358
FWCI: 15.11
Cites: 80
Cited by: 134
Related to: 10