ACE2-independent entry factors for SARS-CoV-2 infection and immune activation

Yiyu Sun; Lok-Yin Roy Wong; Theresa L. Chang

Yiyu Sun, Lok-Yin Roy Wong, Conceptualization Theresa L Chang

mBio, doi:10.1128/mbio.01897-24

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a major public health threat, particularly in vulnerable populations. SARS-CoV-2 spike proteins interact with the human angiotensin-converting enzyme 2 (ACE2) receptor, together with accessory molecules that facilitate viral entry, through its spike receptor-binding domain (RBD). Although ACE2 is the primary receptor required for viral replication, its expression patterns do not fully correlate with viral distribution or tissue pathology. Moreover, SARS-CoV-2 has been shown to infect cells and tissues lacking detectable ACE2 expression. Viral entry via ACE2-independent pathways may also confer resistance to some monoclonal antibodies (Abs) targeting the spike RBD that block ACE2-mediated binding. These observations highlight the potential significance of ACE2-independent entry factors in SARS-CoV-2 infection, particularly in vaccinated individuals with Abs directed against ACE2-dependent viral entry. In this review, we discuss the emerging roles of ACE2-independent entry factors in SARS-CoV-2 infection and the immune responses. These factors include CD147, AXL, CD169/Siglec-1, CD209L, CD209, CLEC4G, ASGR1, LDLRAD3, TMEM30A, TMEM106B, transferrin receptor 1, GPR78, integrin α5β1, KREMEN1, LFA-1, and CD4. While ACE2 remains central to viral replication, ACE2-inde pendent entry appears sufficient to elicit immune responses. Therefore, future inves tigations are warranted to elucidate the roles of ACE2-independent mechanisms in immune-mediated pathology and viral evolution, independent of immune pressure targeting ACE2-mediated entry in previously infected or vaccinated individuals. KEYWORDS SARS-CoV-2, alternative receptors T he coronavirus disease 2019 (COVID-19) pandemic, associated with more than 20 million deaths, was caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) and remains a threat due to the continuous evolution of new variants (1, 2). Vaccinated people remain susceptible to infection by emerging variants (3) (4) (5) (6) , and between 100 and 1,000 COVID-19-related deaths continue to occur each week in the United States in 2025 (7). Although current SARS-CoV-2 variants are less pathogenic than early strains, co-infection of SARS-CoV-2 and influenza virus can have severe disease outcomes (8, 9). Additionally, the emergence of newly evolved strains with better transmissibility and enhanced immune escape poses an ongoing concern. Therefore, a deeper understand ing of the mechanisms underlying SARS-CoV-2 infection is essential for developing more effective preventive and therapeutic strategies to protect vulnerable populations. SARS-CoV-2 entry is primarily mediated by binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor, the entry mechanism of which has been summarized in an excellent review (10). In virus-producing..

AUTHOR AFFILIATIONS Various domains on the spike proteins and E proteins are involved. The interaction of viruses and alternative receptors (e.g., TMEM106B may occur in endosomal compartments). These alternative receptors may play a crucial role in immune activation, particularly in myeloid cells. Additionally, they can act synergistically to facilitate entry of the SARS-CoV-2 E484D variant that is resistant to antibodies targeting RBD through ACE2-mediated viral entry. (B) Alternative receptors can enhance or inhibit ACE2-mediated SARS-CoV-2 entry. The enhancing effect of AXL on ACE2-mediated infection is absent in cells expressing TMPRSS2.

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These observations highlight the potential significance of ACE2-independent entry factors in SARS-CoV-2 infection, particularly in vaccinated individuals with Abs directed against ACE2-dependent viral entry. In this review, we discuss the emerging roles of ACE2-independent entry factors in SARS-CoV-2 infection and the immune responses. These factors include CD147, AXL, CD169/Siglec-1, CD209L, CD209, CLEC4G, ASGR1, LDLRAD3, TMEM30A, TMEM106B, transferrin receptor 1, GPR78, integrin α5β1, KREMEN1, LFA-1, and CD4. While ACE2 remains central to viral replication, ACE2-independent entry appears sufficient to elicit immune responses. Therefore, future investigations are warranted to elucidate the roles of ACE2-independent mechanisms in immune-mediated pathology and viral evolution, independent of immune pressure targeting ACE2-mediated entry in previously infected or vaccinated individuals.\n ", "alternative-id": [ "10.1128/mbio.01897-24" ], "article-number": "e01897-24", "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 3, "value": "2025-12-22" } ], "author": [ { "ORCID": "https://orcid.org/0009-0005-5467-8655", "affiliation": [ { "name": "Rutgers School of Graduate Studies", "place": [ "Newark, USA" ] }, { "name": "Public Health Research Institute", "place": [ "Newark, USA" ] } ], "authenticated-orcid": false, "family": "Sun", "given": "Yiyu", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-0727-8289", "affiliation": [ { "id": [ { "asserted-by": "publisher", "id": "https://ror.org/014ye1258", "id-type": 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