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

Image Credits: AI Generated

EBV was the first virus unequivocally linked to human cancer, a discovery dating back to the 1960s. However, the intricate molecular interplay that underlies its carcinogenic capacity remains elusive. The virus exhibits a remarkable tropism for B lymphocytes, a subset of immune cells, which are crucial not only in mounting immune responses but also represent the cell population from which EBV-induced cancers such as Burkitt’s lymphoma originate. Intriguingly, the role of EBV extends beyond oncogenesis, implicating these infected B cells in the etiology of autoimmune conditions like MS, where the immune system mistakenly targets and degrades the protective myelin sheath enveloping neurons.

A striking feature of EBV infection is its capacity to enter a lifelong latent state within host B cells. This latent reservoir means the virus can evade immune detection and persist indefinitely. Despite this dormancy, the virus is far from inactive; it modulates host cell functions, particularly the migratory behavior of infected B cells. Researchers led by Henri-Jacques Delecluse focused on this phenomenon and discovered that EBV-infected B cells acquire characteristics of "homing cells." These are specialized immune cells capable of transiting from lymphatic vessels through the vascular endothelium to reach target tissues, a tightly regulated process essential for normal immune surveillance.

The novelty of the DKFZ and Heidelberg team’s findings lies in demonstrating that EBV hijacks this homing mechanism, subverting normal cytokine control to facilitate the spread of infected B cells throughout the host organism. This viral manipulation enhances the ability of these cells to traverse the endothelial barrier—a critical checkpoint consisting of tightly joined endothelial cells lining blood and lymph vessels. Such translocation is essential for immune cell trafficking but, when aberrantly induced by EBV, facilitates systemic dissemination of the virus.

Crucially, two viral proteins, EBNA2 and LMP1, have been identified as key drivers of this pathological migration. These proteins stimulate the production of pro-inflammatory cytokines such as CCL4, which are known mediators in inflammatory processes and are particularly relevant in MS pathogenesis. This pro-inflammatory environment not only promotes proliferation of infected B cells but also induces them to cross endothelial barriers—in essence enabling them to “swarm” into various tissues including the brain, where they may trigger or exacerbate autoimmune damage.

The research illuminates a molecular cascade whereby EBNA2 and LMP1 orchestrate chemotactic signaling activating receptors such as CCR1, which are intricately involved in leukocyte trafficking and have been implicated in MS. This receptor-ligand interaction modulates cytoskeletal dynamics and focal adhesion pathways, processes essential for cell motility and diapedesis (the passage of cells through the blood vessel wall). Importantly, the team demonstrated that EBV-induced migration depends on FAK (focal adhesion kinase)-dependent chemotaxis, providing a molecular target for intervention.

Translating these insights into therapeutic avenues, the researchers employed specific inhibitors targeting these pathways in animal models. These interventions successfully suppressed the migration of EBV-infected B cells and reduced their survival rates, effectively limiting viral dissemination within the body and, notably, to the central nervous system. This represents a pioneering step in deploying molecular inhibitors to prevent virus-fueled autoimmunity and tumorigenesis by physically constraining the mobility of infected immune cells.

The implications of these findings are profound. If such inhibitor-based approaches prove effective in humans, they could revolutionize treatment strategies for MS by preventing the infiltration of autoreactive B cells into neural tissue, potentially halting or ameliorating the destructive demyelinating processes characteristic of the disease. Furthermore, this research opens new research frontiers for targeting virus-driven cancers by limiting the invasive capabilities of tumor-associated B cells.

Given that more than 95 percent of adults over 50 years in Germany harbor EBV, with primary infections often asymptomatic in childhood and symptomatic in adults as Pfeiffer’s glandular fever, understanding the viral strategies to evade the immune system and promote dissemination is paramount. The persistent viral reservoir in B cells represents both a challenge and an opportunity for novel antiviral and immunomodulatory therapies aimed at controlling EBV’s pathogenic sequelae.

The study represents a critical convergence of virology, immunology, and neurobiology, elucidating the molecular underpinnings of EBV-induced alterations in immune cell behavior. It exemplifies how pathogens exploit host cellular machinery not only to ensure survival but also to propagate systemic infection and induce disease. Unraveling such viral-host interactions at a cellular and molecular level is instrumental for the development of next-generation therapeutics.

As the German Cancer Research Center continues to pioneer cancer and infection research, collaborations with leading clinical and translational institutes worldwide will be vital in advancing these discoveries from bench to bedside. This promising approach underscores the importance of interdisciplinary research in tackling complex diseases that lie at the intersection of infection, immunity, and chronic illness.

While further clinical studies are essential to validate these findings in human subjects, the DKFZ’s work marks a paradigm shift in understanding EBV’s role in autoimmune disease and cancer. The possibility of pharmacologically inhibiting EBV-induced B cell migration offers hope for millions affected by MS and EBV-associated malignancies, heralding a new era of targeted, molecularly informed therapies.

Subject of Research: Epstein-Barr virus (EBV) influences on immune cell migration and its implications in cancer and multiple sclerosis.

Article Title: Epstein-Barr virus induces aberrant B cell migration and diapedesis via FAK-dependent chemotaxis pathways.

News Publication Date: Not explicitly specified; inferred as 2025 based on publication.

Web References: 10.1038/s41467-025-59813-z

References: S. Delecluse et al. Nature Communications 2025

Keywords: Health and medicine, Epstein-Barr virus, B cell migration, autoimmune disease, multiple sclerosis, viral oncology, immune cell trafficking, cytokines, FAK signaling