Gadanec, Laura Kate ORCID: 0000-0002-4801-8061, McSweeney, K ORCID: 0000-0003-4146-8251, Qaradakhi, Tawar, Ali, Benazir, Zulli, Anthony ORCID: 0000-0002-2660-078X and Apostolopoulos, Vasso ORCID: 0000-0001-6788-2771 (2021) Can SARS-CoV-2 virus use multiple receptors to enter host cells? International Journal of Molecular Sciences, 22 (3). ISSN 1661-6596

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 re-ported 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 immunopatholog-ical 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.

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