Glycocalyx at the host-virus interface: a double-edged sword in virus infection and tissue damage

Viral entry is traditionally viewed as a receptor-mediated event, yet this paradigm overlooks the glycocalyx (GLX) - a dynamic, multifunctional layer of glycans, proteoglycans, and glycolipids that forms the host's first molecular interface with pathogens. Emerging evidence positions the GLX as a bidirectional regulator of infection, capable of both restricting viral access and orchestrating virion capture, receptor clustering, and entry pathway selection. In herpes simplex virus (HSV) infection, cell-type specific GLX architectures on epithelial, endothelial, and immune cells dictate viral tropism, migration, antigen sensing, and immune synapse formation. Infection and inflammation remodel or shed the GLX, perturbing receptor organization, signaling networks, and immune function, thereby contributing to tissue pathology. Beyond its barrier role, the GLX acts as a mechanochemical sensor, integrating environmental cues to coordinate tissue homeostasis and repair. Here, we synthesize recent advances elucidating how GLX composition, spatial organization, and mechanical properties shape viral entry and host responses. We further highlight emerging biomimetic and synthetic strategies to manipulate the GLX, offering new avenues to interrogate virus-host interactions and therapeutic intervention. Collectively, these perspectives redefine the GLX as a central regulator of herpesvirus pathogenesis, functioning simultaneously as a protective shield and facilitator of infection.