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.
Keywords: A549; DPC-333; apratastat; ectodomain shedding; syncytia formation.
【저자키워드】 A549, DPC-333, apratastat, ectodomain shedding, syncytia formation., 【초록키워드】 COVID-19, SARS-CoV-2, pathology, TMPRSS2, Pathogenesis, SARS-COV-2 infection, Infection, variants of concern, protease, in vitro, omicron, syncytia formation, viral entry, Spike protein, antiviral drug, COVID-19 pathogenesis, SARS-CoV-2 variants, SARS-CoV-2 spike protein, human lung, Cell fusion, Alpha, ADAM17, target, Beta, Proteases, inhibitor, A549, apratastat, host cell, causative agent, priming, ectodomain, TMPRSS2 protease, hallmark, facilitator, COVID-19 pathology, Host, Cell, lung cell, host cell factors, ADAM10, identify, required, contribute, expressed, contributing to, reduce, impair, cleave, host cell factor, human lung cell, SARS-CoV-2 cell, the SARS-CoV-2, 【제목키워드】 lung cell, promote, SARS-CoV-2 cell,