Targeting neuroinflammation: itaconate and mesaconate as therapeutic strategies against H7N7 influenza-associated CNS damage

Neither itaconate nor mesaconate significantly altered overall disease severity, as assessed by body weight loss, although mesaconate attenuated infection-associated hypothermia. Pulmonary inflammatory responses were largely unaffected by treatment; in contrast, mesaconate selectively reduced IL-1β levels in the brain. At the cellular level, H7N7 infection induced pronounced microglial activation within hippocampal subregions, characterized by increased cell density and soma volume, altered process complexity, and enhanced engulfment of postsynaptic material. These infection-induced microglial alterations were partially prevented by mesaconate treatment and largely abrogated by itaconate treatment. Notably, attenuation of microglial density and reactivity during the acute phase was associated with long-term preservation of hippocampal synaptic plasticity. Collectively, these findings indicate that therapeutic administration of itaconate and mesaconate, potentially through distinct mechanisms, can modulate microglia-driven synaptic pathology during neurotropic IAV infection. Targeting immunometabolic pathways may therefore represent a promising strategy to prevent persistent neurological sequelae associated with viral disease.