Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells?

• Main Authors: Laura Kate Gadanec, Kristen Renee McSweeney, Tawar Qaradakhi, Benazir Ali, Anthony Zulli, Vasso Apostolopoulos
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: International Journal of Molecular Sciences
• Subjects: <b>Keywords: </b>angiotensin-converting enzyme 2; ACE2; COVID-19; c-lectin type receptor; glucose-regulated protein 78; SARS-CoV-2
• Online Access: https://www.mdpi.com/1422-0067/22/3/992

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.