Broad-spectrum antiviral activity of Ganoderma microsporum immunomodulatory protein: Targeting glycoprotein gB to inhibit EBV and HSV-1 infections via viral fusion blockage

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.