Role of host factors in SARS-CoV-2 entry

Evans, John P.; Liu, Shan-Lu

The zoonotic transmission of highly pathogenic coronaviruses into the human population is a pressing concern highlighted by the ongoing SARS-CoV-2 pandemic. Recent work has helped to illuminate much about the mechanisms of SARS-CoV-2 entry into the cell, which determines host- and tissue-specific tropism, pathogenicity, and zoonotic transmission. Here we discuss current findings on the factors governing SARS-CoV-2 entry. We first reviewed key features of the viral spike protein (S) mediating fusion of the viral envelope and host cell membrane through binding to the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2). We then examined the roles of host proteases including transmembrane protease serine 2 (TMPRSS2) and cathepsins in processing S for virus entry and the impact of this processing on endosomal and plasma membrane virus entry routes. We further discussed recent work on several host cofactors that enhance SARS-CoV-2 entry including Neuropilin-1 (NRP-1), CD147, phosphatidylserine (PS) receptors, heparan sulfate proteoglycans (HSPGs), sialic acid residues, and C-type lectins. Finally, we discussed two key host restriction factors, i.e., interferon-induced transmembrane (IFITM) proteins and lymphocyte antigen 6 complex locus E (Ly6E), which can disrupt SARS-CoV-2 entry. The features of SARS-CoV-2 are presented in the context of other human coronaviruses, highlighting unique aspects. Additionally, we identify the gaps in understanding of SARS-CoV-2 entry that will need to be addressed by future studies.