Zika Virus Reprograms Microglial Mitochondrial Metabolism to Support Immune Activation and Viral Replication: Omega-3...

Microglial cells exhibit crucial metabolic adaptations to maintain neural homeostasis. However, their dysregulated activation during infections can lead to neurotoxicity and contribute to the development of neuroinflammatory disorders. Understanding the physiological and metabolic changes of microglia during immune activation is crucial for identifying protective targets against neuroinflammation. This study investigates how the Zika virus (ZIKV) alters microglia metabolism during inflammation, highlighting cellular adaptations that sustain oxidative metabolism linked to cell survival during cellular activation and viral replication. After identifying an enriched abundance of proteins related to oxidative phosphorylation and cellular component organization in the global proteomics of mouse brains following ZIKV exposure, we investigated the relevance of these pathways during in vitro infection of human microglia. ZIKV infection led to cytoskeleton remodeling via β-tubulin reallocation, which characterized an ameboid-like phenotype. Despite the indication of a shift toward increased glycolytic activity due to decreased intracellular glucose, which suggests its consumption, and the accumulation of tricarboxylic acid cycle (TCA) intermediates, ZIKV-infected microglia exhibit enhanced respiratory capacity and an abundance of smaller-sized mitochondria in the perinuclear region. The accumulation of citrate, succinate, and malate, while maintaining mitochondrial function, suggests an important metabolic adaptation that supports biosynthetic pathways and sustains cell viability under stress. Decreased intracellular glutamate abundance supports mitochondrial oxidative metabolism. Pre-treatment with the anti-inflammatory docosahexaenoic acid (DHA) mitigates ZIKV-induced metabolic alterations by reducing pro-inflammatory markers, downregulating viral entry receptors, and lowering microglial activation and viral load. This study reveals that while ZIKV induces cell death in neuronal-like cells, the mitochondrial adaptation observed in microglial infection could be a key to maintaining cell survival throughout neuroinflammation. Our findings elucidate a novel cellular adaptation during ZIKV infection involving β-tubulin reorganization and metabolic dynamics, reflecting microglial flexibility and resistance during neuroinflammation, and demonstrating the therapeutic potential of DHA in mitigating ZIKV-induced pathology.