Innate immunity-mediated inflammation and immunopathogenesis in HSV-1-infected encephalitis.

Abstract

HSV-1 encephalitis (HSE) remains a devastating viral infection of the central nervous system despite effective antiviral therapy. Increasing evidence indicates that disease outcome is not determined by viral replication alone but by how innate immunity is calibrated within the brain. Studies of host susceptibility in childhood HSE have identified brain-intrinsic antiviral mechanisms, referring to central nervous system (CNS)-localized innate immune pathways that enable resident brain cells to sense and restrict HSV-1 infection, particularly TLR-dependent interferon responses, neuron-associated restriction factors, and other CNS-resident innate immune mechanisms. Host innate immune responses initially contribute to viral restriction, whereas excessive or unresolved activation can promote inflammatory amplification and long-term neurological injury. In parallel, HSV-1-mediated immune remodeling may weaken antiviral control and alter the subsequent inflammatory trajectory. Here, HSE is discussed as a dynamic immunopathological disorder in which protective innate immunity can transition into pathogenic neuroinflammation. Building upon these observations, we propose that host-directed therapeutic strategies should shift from uniform immune modulation toward stage-specific immune recalibration on the basis of viral control, antiviral competence, inflammatory persistence, and tissue repair.