The Chrono-Immunological Axis in Viral Encephalitis: Circadian Clocks, Melatonin, and Dynamic Microglial States

Viral encephalitis is a severe neurological condition in which direct viral injury and dysregulated neuroimmune responses jointly determine disease progression and long-term outcomes. Microglia are central to this process, supporting antiviral defense and tissue repair while also contributing to excessive inflammation and neuronal damage. Growing evidence indicates that microglial functions and antiviral immunity are temporally regulated by molecular circadian clocks. Melatonin may connect these systems through its chronobiotic, immunomodulatory, antioxidant, and mitochondrial effects. This comprehensive review examines whether melatonin and circadian clock pathways modulate microglial states and functions during viral encephalitis. We integrate evidence from neurotropic viral infections, experimental encephalitis models, and mechanistic studies of clock–immune interactions, with emphasis on CLOCK–BMAL1, PER–CRY, REV-ERB–ROR, NF-κB, type I interferon, and NLRP3 signaling. Current findings suggest that the effects of melatonin are context-dependent and may vary according to viral species, dose, circadian phase, cellular target, and disease stage. Although preclinical observations support the individual components of a potential chrono-immunological framework, evidence directly integrating these components remains limited. Future studies should incorporate time-of-day-controlled designs, dynamic microglial phenotyping, and stage-specific melatonin administration. Understanding this axis may enable more precise chronotherapeutic strategies that preserve antiviral immunity while limiting neuroinflammatory injury.