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.

Interferon epsilon (IFNε), a unique type I IFN, is highly abundant in the female reproductive tract (FRT). Unlike IFNα and IFNβ, which are expressed at low or undetectable levels at the baseline and are strongly induced following pattern-recognition receptor activation, IFNε is constitutively expressed in the epithelium at mucosal tissues. Its expression is regulated by hormones and inflammatory cytokines. Its responsiveness to viral infection and Toll-like receptor activation varies across cell types. This distinctive regulatory profile positions IFNε as a preemptive component of mucosal defense. Studies in mice and human FRT tissues have established important roles for IFNε in maintaining expression of genes involved in epithelial and tissue structure as well as basal interferon-stimulated genes restricting sexually transmitted pathogens, including herpes simplex virus-2, Chlamydia, human immunodeficiency virus, and Zika virus. IFNε also shapes local immune responses, including uterine natural killer-cell recruitment and activation. However, its effects are not uniformly protective: Neisseria gonorrhoeae can exploit IFNε-dependent changes in sialic-acid metabolism to promote persistence. Recent work further broadens the IFNε paradigm beyond antimicrobial defense. IFNε-deficient mice exhibit cervicovaginal epithelial abnormalities and altered antiviral epithelial states, while IFNε has emerged as an intrinsic tumor suppressor in the fallopian tube/ovarian cancer axis. Human studies also implicate IFNε in pregnancy, cervical HPV responses, and cervical cancer, although the direction and mechanisms of these associations remain unknown. Here, we review the expression, regulation, signaling, and biological functions of IFNε in the FRT, reconcile emerging evidence for tissue- and context-specific actions, and discuss key unanswered questions concerning epithelial homeostasis, receptor usage, reproductive physiology, infection, and gynecologic malignancy.