31 research outputs found
ADAM10 and ADAM17 promote SARSâCoVâ2 cell entry and spike proteinâmediated lung cell fusion
The severeâacuteârespiratoryâsyndromeâcoronavirusâ2 (SARSâCoVâ2) is the causative agent of COVIDâ19, but host cell factors contributing to COVIDâ19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARSâCoVâ2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVIDâ19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARSâCoVâ2 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 proteaseâtargeted inhibitors severely impair lung cell infection by the SARSâCoVâ2 variants of concern alpha, beta, delta, and omicron and also reduce SARSâCoVâ2 infection of primary human lung cells in a TMPRSS2 proteaseâindependent 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
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