AbstractIntricate interactions of virus and host factors define the ability of a virus to infect the host and spread across tissues, ultimately affecting pathogenicity and disease outcome. Hence the mechanistic understanding of such interactions is of utmost importance for the discovery of novel antivirals. The causative agent of the COVID-19 pandemic, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), uses the viral spike protein (S) for host cell entry via its receptor Ace2. An important distinctive feature of SARS-CoV2 S protein is a cleavage site for host protease furin, which processes S to generate a carboxy-terminal polybasic sequence in the resultant peptide. This sequence appears to be a recognition and activation motif for another cellular receptor, neuropilin-1 (Nrp1). We found that Nrp1 binds to the furin-cleaved S protein and significantly promotes SARS-CoV2 infectivity in cell culture. The inhibition of Nrp1, on the contrary, limits SARS-CoV2 infection. Nrp1 is abundantly expressed in pulmonary, olfactory, and endothelial cells and thus can be an essential co-factor for SARS-CoV2 cell entry and tissue tropism. Pathological analysis of olfactory epithelium from human COVID-19 autopsies corroborated this finding, revealing SARS-CoV-2 infection in Nrp1 positive cells lining the nasal cavity. Thus, our data provide insight into SARS-CoV2 infectivity, tissue tropism, and pathogenesis, suggesting that S-Nrp1 interaction could be a potential target for antiviral intervention.