ACE2-Independent Alternative Receptors for SARS-CoV-2

• Published in: Viruses Vol. 14; no. 11; p. 2535
• Main Authors: Lim, Suhyeon, Zhang, Monica, Chang, Theresa L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16-11-2022; MDPI
• Subjects: ACE2; alternative receptors; Angiotensin; Angiotensin converting enzyme; Angiotensin-Converting Enzyme 2; Axl protein; CD147 antigen; Cell receptors; Coronaviruses; COVID-19; DC-SIGN protein; Humans; Internalization; Kinases; Monoclonal antibodies; Peptidyl-dipeptidase A; Physiological aspects; Public health; Receptors, Virus; Review; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Tropism; Viral infections; Virus attachment; Virus Internalization; United States; SARS-CoV-2; alternative receptors
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v14112535

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is highly contagious and remains a major public health challenge despite the availability of effective vaccines. SARS-CoV-2 enters cells through the binding of its spike receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 (ACE2) receptor in concert with accessory receptors/molecules that facilitate viral attachment, internalization, and fusion. Although ACE2 plays a critical role in SARS-CoV-2 replication, its expression profiles are not completely associated with infection patterns, immune responses, and clinical manifestations. Additionally, SARS-CoV-2 infects cells that lack ACE2, and the infection is resistant to monoclonal antibodies against spike RBD in vitro, indicating that some human cells possess ACE2-independent alternative receptors, which can mediate SARS-CoV-2 entry. Here, we discuss these alternative receptors and their interactions with SARS-CoV-2 components for ACE2-independent viral entry. These receptors include CD147, AXL, CD209L/L-SIGN/CLEC4M, CD209/DC-SIGN/CLEC4L, CLEC4G/LSECtin, ASGR1/CLEC4H1, LDLRAD3, TMEM30A, and KREMEN1. Most of these receptors are known to be involved in the entry of other viruses and to modulate cellular functions and immune responses. The SARS-CoV-2 omicron variant exhibits altered cell tropism and an associated change in the cell entry pathway, indicating that emerging variants may use alternative receptors to escape the immune pressure against ACE2-dependent viral entry provided by vaccination against RBD. Understanding the role of ACE2-independent alternative receptors in SARS-CoV-2 viral entry and pathogenesis may provide avenues for the prevention of infection by SARS-CoV-2 variants and for the treatment of COVID-19.