Role of host factors in SARS-CoV-2 entry

Abstract

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. We then examined the roles of host proteases including transmembrane protease serine 2 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, CD147, phosphatidylserine receptors, heparan sulfate proteoglycans, sialic acids, and C-type lectins. Finally, we discussed two key host restriction factors, i.e., interferon-induced transmembrane proteins and lymphocyte antigen 6 complex locus E, 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. In addition, we identify the gaps in understanding of SARS-CoV-2 entry that will need to be addressed by future studies.

Keywords: ACE2; RNA virus; SARS-CoV-2; TMPRSS2; cathepsin B; endocytosis; entry cofactor; membrane fusion; virus entry; virus receptor.

Figure 1

SARS-CoV-2 Spike contains a furin cleavage motif at S1/S2 cleavage site.Top, schematic of the SARS-CoV-2 Spike protein with S1 subunit, S2 subunit, receptor binding domain (RBD), fusion peptide, transmembrane domain, S1/S2 cleavage site, and S2’ cleavage site indicated. Bottom, alignment of SARS-CoV-2 S1/S2 and S2’ cleavage sites with corresponding regions of S protein from related bat coronaviruses (BaCoV) and other human coronaviruses. The phylogenetic tree indicates the relatedness of full-length S proteins. The RXXR furin cleavage motif at the S1/S2 site is indicated for SARS-CoV-2 and is present in MERS-CoV, HCoV-OC43, and HCoV-HKU1. The site of cleavage is indicated with an arrowhead. Sequence IDs are indicated next to the virus names and correspond to NCBI accession numbers or GISAID accession numbers. Alignment and phylogenetic tree were produced using full-length S protein sequence alignment with ClustalOmega (130).

Figure 2

SARS-CoV-2 attachment cofactors can enhance virus entry via the endosomal entry route and the plasma membrane entry route. Binding of virions to the representative attachment cofactors can facilitate SARS-CoV-2 S binding to ACE2. Then subsequent cleavage by cell surface TMPRSS2 can lead to cell membrane fusion, or endocytosis of SARS-CoV-2 allows for cathepsin B/L processing of SARS-CoV-2 S and subsequent fusion both in an ACE2-dependent manner. Whether or not TMPRSS2 processing could influence endosomal entry is currently unknown.