In a groundbreaking advancement in virology, scientists have unveiled the elusive mechanism by which Epstein–Barr virus (EBV), a pervasive human herpesvirus, infects epithelial cells. This discovery centers on the identification of desmocollin 2 (DSC2) as the principal receptor facilitating EBV entry into epithelial cells—a critical insight that reshapes our understanding of EBV transmission and paves the way for novel therapeutic interventions. EBV, long recognized for infecting B lymphocytes and epithelial cells, has posed an enigma due to the inefficiency of cell-free infection in epithelial tissues despite their susceptibility in vivo. The research unravels this paradox, highlighting the importance of direct cell-to-cell contact and the pivotal role of DSC2 in enabling efficient viral spread.
EBV is notorious for its dual tropism, infecting both B cells and the epithelial linings of the oropharynx. While infection of B cells has been extensively studied, epithelial infection mechanisms have remained less clear. Historically, EBV infection of epithelial cells using free viral particles was shown to be inefficient in laboratory settings, yet clinical manifestations suggest otherwise. Prior to this study, some candidates like EphA2 had been proposed as receptors facilitating epithelial infection, but their roles were inconsistent and failed to fully explain infection dynamics. The present study, utilizing an innovative genome-wide CRISPR-Cas9 screen, identified DSC2 as a receptor indispensable for the viral entry process in epithelial cells.
The researchers conducted a comprehensive CRISPR screen aimed at pinpointing host factors that facilitate EBV entry into epithelial cells. This unbiased approach allowed them to systematically disable genes and observe the consequences on EBV infection efficiency. Through meticulous analysis, DSC2 emerged as a top candidate, with its knockout resulting in a significant decrease in viral infection rates. Intriguingly, desmocollin 3 (DSC3), a protein closely related to DSC2, was also implicated as a co-factor, not merely a redundant homolog. Together, DSC2 and DSC3 form a critical entry complex, necessary for both cell-free and — importantly — cell-to-cell contact infection modes.
Building on these genetic insights, the team then employed loss- and gain-of-function experiments to validate DSC2’s role. Keratinocytes deficient in DSC2 and DSC3 showed a pronounced reduction in infection rates, both when exposed to cell-free viral particles and when co-cultured with EBV-infected B cells. Moreover, overexpressing DSC2 and DSC3 in receptor-negative cells significantly enhanced their susceptibility to infection, providing compelling evidence of their sufficiency and necessity. This dual requirement hints at a sophisticated viral entry mechanism optimized for the unique architecture of epithelial tissues, which are characterized by intricate cell-to-cell contacts.
The therapeutic potential of targeting DSC2 was elegantly demonstrated by the application of monoclonal antibodies aimed at this protein. When epithelial cells were treated with antibodies directed at DSC2, EBV infection was markedly inhibited across a range of models, including normal oral keratinocytes, primary oral keratinocytes, and advanced head and neck epithelial organoids. The blockade effect became even more pronounced with a combination of antibodies against both DSC2 and DSC3, which efficiently suppressed the intimate cell-to-cell viral transfer that likely dominates natural infections. This points toward DSC2 as a highly promising target for preventative strategies, including vaccine development and antibody-based therapeutics.
Mechanistically, DSC2’s interaction with the viral glycoprotein complex gH/gL was interrogated to unravel the intricacies of EBV fusion and entry. The study found that DSC2 directly binds to gH/gL, facilitating the membrane fusion process that enables viral capsid delivery into the host cytoplasm. This interaction is critical, as it orchestrates the structural rearrangements needed for EBV to breach the epithelial cell membrane. Interestingly, attempts to rescue infection in cells lacking DSC2 and DSC3 by overexpressing EphA2, a previously proposed EBV receptor, failed—highlighting a dependency hierarchy and confirming DSC2/3 as the dominant receptor complex for epithelial infection.
The implication of these findings extends beyond basic virology, impacting our understanding of EBV-associated malignancies. EBV’s ability to exploit the DSC2 receptor complex for infection suggests that disruptions or variations in desmosomal components could influence susceptibility to infection and subsequent oncogenic transformation. Since EBV is causally linked to several epithelial malignancies, including nasopharyngeal carcinoma and certain head and neck cancers, targeting the DSC2 interaction axis holds potential not just for infection prophylaxis but also for interrupting oncogenic progression.
Furthermore, the discovery refines the model of EBV pathogenesis within the oral cavity and oropharynx. The efficient transmission via direct B cell and epithelial cell contact underscores the significance of tissue architecture and cellular microenvironments in viral persistence and dissemination. EBV’s preference for this contact-mediated route rather than relying solely on cell-free virions explains longstanding clinical observations and reconciles previous inconsistencies in in vitro infection studies. This study thus bridges significant gaps in viral epidemiology and transmission dynamics.
The application of advanced organoid culture systems in this research represents a leap forward in modeling EBV infection in near-physiological conditions. Head and neck epithelial organoids, which recapitulate the complex differentiation and stratification of epithelial tissues, allowed for more accurate assessment of viral entry and spread. The successful inhibition of infection in these organoids using DSC2-targeting antibodies strengthens the translational prospects of these findings, indicating that therapeutic strategies developed in vitro may be applicable in vivo.
This study also raises fascinating questions about the broader role of desmosomal cadherins in viral infections. Desmocollins like DSC2 and DSC3 are key components of desmosomes, structures critical for cellular adhesion and tissue integrity. Viruses co-opting these proteins for entry point to a possible convergence of cell adhesion pathways and viral invasion mechanisms. This cross-talk may be exploited by other pathogens and represents a fertile ground for future research exploring host-microbe interactions at cellular junctions.
Moreover, the elucidation of DSC2 as a primary receptor challenges prior paradigms that focused on other molecules such as integrins and Eph receptors. By highlighting a direct interaction with the viral glycoprotein complex, this study reorients therapeutic design toward desmosomal proteins, which may have been previously underappreciated. This shift in focus may inspire the generation of novel antiviral drugs that interfere specifically with the fusion process facilitated by DSC2-gH/gL binding.
Given the ubiquitous prevalence of EBV and its association with a spectrum of diseases ranging from infectious mononucleosis to malignancies, the identification of DSC2 as the principal epithelial entry receptor offers a universal target. This could translate into the development of broadly applicable vaccines or monoclonal antibody therapies that prevent initial infection or limit viral spread, significantly impacting global health. In the future, clinical trials targeting DSC2 may redefine EBV management, shifting from symptomatic treatment to direct infection blockade.
In summary, this pioneering work sheds light on the molecular underpinnings of EBV epithelial infection, introducing desmocollin 2 as the linchpin receptor that facilitates viral entry via direct cell-to-cell contact. The reliance on DSC2 and DSC3 for infection, the demonstrable blockade via antibodies, and the failure to rescue infection through alternative receptors compel a reevaluation of EBV biology. These discoveries have far-reaching implications for virology, oncology, and therapeutic development, marking a paradigm shift in the battle against this ubiquitous virus.
The comprehensive investigation by Wang et al. not only clarifies the elusive mechanism of EBV epithelial infection but also inspires an array of future research directions. Understanding the structural basis of the DSC2-gH/gL interaction, exploring how desmosomal integrity influences EBV pathogenesis, and translating these findings into clinical applications are poised to transform the landscape of EBV prevention and treatment. This study epitomizes the power of integrative genomic screening and cellular modeling in unraveling complex viral-host interactions.
As scientists continue to unravel the complexities of EBV’s interactions with its human host, the identification of desmocollin 2 as a principal entry receptor is a milestone achievement. It underscores the intricate interplay between viral evolution and host cell biology, revealing how viruses have adapted to exploit cellular machinery to ensure survival and propagation. This breakthrough serves as a blueprint for tackling other viral pathogens with similarly enigmatic infection mechanisms, showcasing how cutting-edge technologies can illuminate biological mysteries with profound clinical impact.
Subject of Research: The molecular mechanisms underlying Epstein–Barr virus (EBV) infection of epithelial cells, focusing on the identification of desmocollin 2 (DSC2) as the principal EBV epithelial receptor and the role of desmocollin 3 (DSC3) as a co-factor.
Article Title: Epstein–Barr virus exploits desmocollin 2 as the principal epithelial cell entry receptor.
Article References:
Wang, H., Mou, Z., Yeo, Y.Y. et al. Epstein–Barr virus exploits desmocollin 2 as the principal epithelial cell entry receptor. Nat Microbiol (2025). https://doi.org/10.1038/s41564-025-02126-0
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