The Epstein-Barr virus (EBV) establishes lifelong B cell infection via oral transmission; however, it paradoxically drives carcinomas in anatomically distant organs with striking geographic disparities. While genomic studies frequently link specific EBV variants to these epithelial cancers, the mechanisms bridging ubiquitous infection to distant, strain-dependent malignancies remain largely unresolved. Using an induction-free primary B cell system, we identify a circulating B cell-vector pathway driving immortalized epithelial dissemination. We demonstrate that B cells infected with carcinoma-associated strains exhibit markedly higher epithelial transmission compared with those carrying lymphoid strains. This contact-dependent process requires spontaneous lytic reactivation, viral DNA replication, and de novo virion production. Crucially, those infected B cells retain their transmission capacity for months, supporting sustained epithelial seeding. Mechanistically, entry requires gH/gL engagement of EphA2/desmocollin-2 (DSC2), with actin- and PI3K-dependent endocytosis. These findings define a lytic-coupled, receptor-dependent pathway by which the EBV exploits B cells to access the epithelium, offering a mechanistic framework for understanding strain tropism and host-virus interactions.
Epstein-Barr virus (EBV) and herpes simplex virus-1 (HSV-1) are members of the Herpesviridae family and cause various human malignancies and acute infections. Despite their clinical significance, effective treatments remain limited. Here, we report the broad-spectrum antiviral activity of Ganoderma microsporum immunomodulatory protein (GMI), a safe dietary ingredient known for its immunomodulatory, anti-tumor, and antiviral properties. GMI effectively blocks EBV infection in epithelial cells in a dose-dependent manner by targeting both viral and host cells. Notably, GMI displays antiviral activity across multiple EBV strains in epithelial cell infection and represses EBV infection in primary B cells. Mechanistically, GMI interacts with the EBV fusion glycoprotein gB and the host epithelial receptor EphA2 to disrupt viral fusion. Given the structural conservation of gB among herpesviruses, GMI was tested against HSV-1. Remarkably, GMI effectively blocks HSV-1 infection by targeting viral binding and fusion, as well as interacting with HSV-1 gB. In silico modeling suggests that GMI may interact with EBV and HSV-1 gB domain I, contributing to its antiviral activity. Our findings provide the first evidence that GMI suppresses both EBV and HSV-1 infections by targeting the conserved gB-mediated fusion process, suggesting its potential as an antiviral against herpesviruses that rely on fusion-mediated entry.