Neuropilin-1 is a host factor for SARS-CoV-2 infection

Daly, James L.; Simonetti, Boris; Antón-Plágaro, Carlos; Kavanagh Williamson, Maia; Shoemark, Deborah K.; Simón-Gracia, Lorena; Klein, Katja; Bauer, Michael; Hollandi, Reka; Greber, Urs F.; Horvath, Peter; Sessions, Richard B.; Helenius, Ari; Hiscox, Julian A.; Teesalu, Tambet; Matthews, David A.; Davidson, Andrew D.; Cullen, Peter J.; Yamauchi, Yohei

SARS-CoV-2 is the causative agent of COVID-19, a coronavirus disease that has infected more than 6.6 million people and caused over 390,000 deaths worldwide1,2. The Spike (S) protein of the virus forms projections on the virion surface responsible for host cell attachment and penetration. This viral glycoprotein is synthesized as a precursor in infected cells and, to be active, must be cleaved to two associated polypeptides: S1 and S2(3,4). For SARS-CoV-2 the cleavage is catalysed by furin, a host cell protease, which cleaves the S protein precursor at a specific sequence motif that generates a polybasic Arg-Arg-Ala-Arg (RRAR) C-terminal sequence on S1. This sequence motif conforms to the C-end rule (CendR), which means that the C-terminal sequence may allow the protein to associate with cell surface neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors5. Here we demonstrate using immunoprecipitation, site-specific mutagenesis, structural modelling, and antibody blockade that, in addition to engaging the known receptor ACE2, S1 can bind to NRP1 through the canonical CendR mechanism. This interaction enhances infection by SARS-CoV-2 in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection, and provides a therapeutic target for COVID-19.