FOXO1a and IL10/IL10rb-associated responses coordinate myelin preservation and immune–redox homeostasis during viral neuroinflammation

Neurotropic viral infections can cause rapid neurological deterioration, but disease severity reflects pathogen burden and the capacity of neural tissues to tolerate infection-associated stress. Using a zebrafish larval model of nervous necrosis virus (NNV) infection, we found that early infection induced myelin abnormalities, inflammatory activation, redox and iron dyshomeostasis, and reduced expression of oligodendrocyte-lineage and myelin-associated markers. Genetic ablation of foxo1a or il10rb increased viral burden and exacerbated inflammatory, oxidative, ferroptosis-associated, and myelin-related abnormalities, whereas genetic rescue partially restored these phenotypes. FOXO1a increased il10 promoter-reporter activity in a heterologous system, and il10 supplementation partially restored socs3 , mbp , and gpx4 expression while reducing tnfα expression in foxo1a-deficient larvae. In contrast, il10 supplementation failed to restore the expression of above three marker genes in il10rb-deficient larvae. Pharmacological modulation of FOXO-related stress responses or lipid peroxidation during infection partially preserved myelin ultrastructure, improved larval survival, and reduced viral readouts. Collectively, these findings support a coordinated FOXO1a- and IL10/IL10rb-associated protective network, though it may not operate through a strictly linear signaling cascade, that actively maintains immune-redox homeostasis and myelin preservation during acute NNV infection. These results further suggest that prioritizing anti-inflammatory pathway activation to sustain immune equilibrium, rather than solely targeting viral clearance, could represent a more effective therapeutic strategy for mitigating neurotropic viral pathogenesis.