Abstract
The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.
Highlights
Betacoronavirus is one of four genera of coronaviruses, which are enveloped positive stranded RNA viruses, and require humans and other mammals as hosts to replicate
The natural host of betacoronaviruses are rodents and bats [1,2]. These viruses are of particular clinical importance for humans as they are known to infect humans and cause disease, including human coronavirus HKU1 and OC43, which cause the common cold, and severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2, which is responsible for coronavirus disease 2019 (COVID-19) [1,3]
We propose that SARS-CoV-2 S protein is a pathogen-associated molecular patterns (PAMP) internalized by TLR4, through identification and interaction with surface glycan and mannose carbohydrate motifs on the subunit 1 (S1)
Summary
Betacoronavirus is one of four genera of coronaviruses (alpha, beta, gamma, delta), which are enveloped positive stranded RNA viruses, and require humans and other mammals as hosts to replicate. There was a theoretical endorsement that the increase of ACE2 by the indirect effects of AngII receptor blockers (ARB) and ACE inhibitors taken by patients with CVD and related comorbidities, could enhance docking sites for SARS-CoV-2, leading to severe COVID-19 [17,18]. ACE2 deficiency [31,32,33] or absence [32], suggesting that the S protein exploits additional receptors to gain entry into host cells leading to systemic infection [2,34,35]. Ezrin [37], and dipeptidyl peptidase-4 (DPP4) [38] have been postulated to be targets against SARS-CoV-2, but have yet to be confirmed in in vitro and in vivo models These receptors and proteins may represent alternative routes for viral infection by facilitating receptor-dependent internalization of the S protein (Figure 1).
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