Abstract
The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.
Highlights
A n outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has caused a pandemic associated with a severe acute pulmonary disease named COVID-19 [1]
We compared the ability of WT and mutant SARS-CoV-2 to infect HEK-293T that stably express angiotensinconverting enzyme 2 (ACE2); ACE2 and transmembrane protease serine 2 (TMPRSS2); or ACE2, TMPRSS2, and NRP1
We studied the effect of the NRP1-blocking antibody, mAb3, on infection of Caco-2 cells by WT and mutant SARSCoV-2 and found that preincubation with NRP1-blocking antibody reduced WT virus infection by ~40%, whereas the control mAb2 had no effect (Fig. 2, G and H)
Summary
Validated that exogenous ACE2 expression rendered HEK-293T cells susceptible to infection with SARS-CoV-2 (Fig. 2, C and D). We compared the ability of WT and mutant SARS-CoV-2 to infect HEK-293T that stably express ACE2; ACE2 and TMPRSS2; or ACE2, TMPRSS2, and NRP1 Infection of these cell lines by the WT, but not the mutant, virus increased in the presence of NRP1, providing further evidence that NRP1 requires a furin-cleaved substrate for its effects (Fig. 2, E and F). Cleavage of SARS-CoV-2 S protein at the S1-S2 site generates the C-terminal end sequence TQTNSPRRAROH To determine whether this specific sequence can function as a substrate for NRP1, we used AgNPs coated with TQTNSPRRAROH peptide or different control peptides, including one with a terminal amide group (TQTNSPRRARNH2), which reduces NRP1 binding [9] (Fig. 3A). Whereas ACE2 was detected at very low levels, both NRP1 and NRP2 were abundantly expressed in almost all pulmonary and olfactory
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