In a groundbreaking advance in virology, researchers have unveiled a pivotal mechanism by which Epstein–Barr virus (EBV) infiltrates epithelial cells, shedding new light on the pathogenesis of EBV-related malignancies. EBV, a ubiquitous herpesvirus, is well-known for its ability to infect both B lymphocytes and epithelial cells, the latter of which contributes to cancers such as nasopharyngeal carcinoma and gastric carcinoma. While prior studies have elucidated aspects of EBV entry into B cells, the precise molecular interactions facilitating epithelial cell infection have remained elusive, hindering efforts to develop targeted interventions and representative animal models.
At the center of this discovery is desmocollin 2 (DSC2), an adhesion molecule traditionally known for its role in the desmosomal junctions that fortify epithelial tissue integrity. Employing a state-of-the-art CRISPR–Cas9 screening approach, scientists systematically disrupted candidate genes in epithelial cell lines to identify those essential for EBV entry. DSC2 emerged strikingly as a dominant receptor mediating viral infection, a finding that was validated through a series of rigorous functional assays.
The experimental ablation of the DSC2 gene in nasopharyngeal and gastric epithelial cells resulted in a pronounced reduction of EBV infection rates. This loss of susceptibility was not irreversible: reintroduction of DSC2 into knockout cells fully restored their vulnerability to the virus, underscoring the receptor’s indispensable role. Moreover, the expression of human DSC2 in hamster epithelial cells—normally refractory to EBV—rendered these cells permissive, definitively demonstrating DSC2’s sufficiency to confer viral entry capability across species barriers.
Delving deeper into molecular interactions, the researchers characterized the binding affinity between EBV’s viral glycoprotein complex—specifically glycoprotein H (gH) and glycoprotein L (gL)—and DSC2. Using biochemical assays and binding studies, they pinpointed the extracellular domains of DSC2, notably the preEC and EC2 regions, as critical interfaces for viral attachment. This direct interaction was shown to be targetable with polyclonal antibodies raised against these epitopes, which successfully blocked EBV infection in primary human epithelial cells, an encouraging finding for therapeutic strategies.
An intriguing aspect of this work is the revelation that DSC2 mediates EBV entry independently of Ephrin receptor A2 (EphA2), a receptor previously implicated in EBV infection of epithelial cells. The data suggest that DSC2 represents a dominant or perhaps primary gateway, whereas EphA2 may act as a facilitator or a secondary receptor under certain physiological contexts. This insight refines the conceptual landscape of EBV tropism and points toward receptor-specific intervention bundles.
The identification of DSC2 as a key EBV entry receptor is not merely a mechanistic detail; it has broad implications for model organism development. The lack of suitable animal models has long stymied the comprehensive understanding of EBV pathogenesis and the testing of antiviral therapies. By artificially expressing DSC2 in non-permissive species, researchers may now be able to engineer better in vivo platforms that recapitulate human epithelial infection dynamics, accelerating translational research.
Furthermore, the study’s findings could ignite a new wave in antiviral drug discovery. Targeting the DSC2–gH/gL interaction offers a promising therapeutic avenue to block initial infection or prevent viral spread among epithelial cells. The neutralizing capacity of antibodies against the DSC2 extracellular domain highlights the feasibility of this approach and suggests potential for vaccine design or antibody-based therapeutics.
The utilization of CRISPR–Cas9 screening in this context exemplifies the power of modern genomics tools to disentangle complex virus-host interfaces. By systematically probing the host cell surface proteins required for EBV entry, the researchers bypassed traditional candidate-based approaches, enabling unbiased discovery. This methodology heralds a paradigm shift for identifying viral receptors in other persistent and oncogenic viruses as well.
From a clinical perspective, EBV-associated epithelial malignancies remain notoriously difficult to treat once established, partly due to their complex virology and interplay with host factors. Understanding that DSC2 plays a central role in infection opens the door for early intervention strategies aimed at disrupting viral establishment in epithelial tissues, potentially reducing the incidence of EBV-driven cancers.
Moreover, the research emphasizes the interplay between the virus and cell adhesion molecules, balancing the virus’s need for stable attachment with the tissue’s architectural integrity. Desmocollins such as DSC2 are integral to desmosomes, structures that confer mechanical stability to epithelia. The virus’s exploitation of DSC2 hints at a sophisticated evolutionary strategy, wherein EBV co-opts essential cellular molecules for entry without overtly compromising tissue barriers—a delicate equilibrium favoring persistent infection.
The specificity of DSC2 binding to EBV gH/gL also raises intriguing questions about viral adaptation and species specificity. The ability to confer susceptibility in hamster cells through DSC2 expression suggests a conserved pathway amenable to genetic manipulation. This could facilitate cross-species viral studies and elucidate viral entry mechanics at a granular level, potentially uncovering additional host factors involved in post-entry steps.
While this study advances the field considerably, it also sets the stage for future research to explore the structural biology of the DSC2-gH/gL complex at atomic resolution. Such insights could inform rational vaccine design or the development of small-molecule inhibitors that disrupt key contact points. Furthermore, understanding how DSC2-mediated entry intersects with intracellular signaling cascades may reveal novel aspects of EBV pathogenesis and immune evasion.
In sum, the identification of desmocollin 2 as a dominant epithelial entry receptor reshapes our understanding of Epstein–Barr virus biology. This discovery not only resolves long-standing questions about receptor usage in epithelial infection but also paves the way for innovative therapeutic and modeling approaches. By illuminating this critical viral ingress pathway, researchers have significantly advanced the frontier of EBV virology, potentially transforming clinical paradigms in the management of EBV-associated epithelial malignancies.
Subject of Research: Epstein–Barr virus entry mechanisms and receptor identification in epithelial cells
Article Title: Desmocollin 2 is a dominant entry receptor for Epstein–Barr virus infection of epithelial cells
Article References:
Zhang, H., Li, YC., Pang, D. et al. Desmocollin 2 is a dominant entry receptor for Epstein–Barr virus infection of epithelial cells. Nat Microbiol (2025). https://doi.org/10.1038/s41564-025-02067-8
Image Credits: AI Generated
