The availability of virus receptors and cofactors on host cells’ surface often determines viruses’ tissue tropism and may explain the difference in spreading between SARS-CoV and SARS-CoV-2. Despite the cellular receptor angiotensin-converting enzyme 2 (ACE2) mediating the uptake of both SARS-CoV and SARS-CoV-2, SARS-CoV led to a much smaller outbreak in 2003.
The expression pattern of ACE2 in tissue also does not match the virus’s tissue tropism, raising the possibility that cofactors are required to facilitate virus-host interactions. SARS-CoV-2 contains an S1/S2 site containing multiple arginine residues that is a substrate for the cellular protease furin. Neuropilin-1 is known to bind furin cleaved substrates and may serve as a cell surface entry cofactor.
In a recent study in Science, L. Cantuti-Castelvetri et al. measured the uptake of lentivirus particles in HEK cells using immunofluorescence and qPCR. They observe a markedly enhanced infection of HEK cells coexpressing NRP1 with ACE2 or transmembrane protease serine 2 (TSS2). Cleavage of the SARS-CoV-2 protein at the S1/S2 site generates a C-terminal sequence that the authors tested as a substrate for NRP1 in both HEK-293T cells and mouse olfactory epithelium. Fluorescence imaging of nanoparticles labeled with the fluorescent dyes CF®555 or CF®647 and coated with SARS-CoV-2 derived C terminal peptides shows the specificity of the uptake mediated by NRP1 (see Fig).
The expression patterns of ACE2 and NRP1 from published scRNA-seq datasets of human lung tissue show that the pulmonary and olfactory epithelium abundantly expresses NRP1 and NRP2 while ACE2 is hardly detectable in these tissues. Examining NRP1 immunoreactivity in human autopsy tissue confirmed the co-localization of the viral spike protein and the expression of NRP1. From these results, NRP-1 appears to be a candidate for an ACE2 potentiator.
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Full Citation
L. Cantuti-Castelvetri et al. (2020), Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity Science https://doi.org/10.1126/science.abd2985