Lactate accumulation triggered by RNA virus infection facilitates viral replication

As the terminal product of glycolysis, lactate has emerged as a crucial signaling molecule mediating metabolic reprogramming with immune regulation. Although RNA viruses are known to exploit host metabolism, the precise role of lactate accumulation in viral pathogenesis remains to be fully elucidated. Using Newcastle disease virus and influenza A virus as model pathogens, this study demonstrates that RNA virus infection rapidly activates host glycolysis and induces sustained lactate accumulation, thereby creating a microenvironment favorable for viral replication. Pharmacological inhibition of glycolysis markedly suppressed viral proliferation. In inhibition-rescue experiments, exogenous lactate supplementation reversed the antiviral immune gene and IRF3-phosphorylation changes induced by glycolytic inhibition. Adding exogenous sodium lactate without inhibiting glycolysis further repressed antiviral immune gene expression and IRF3 phosphorylation. Mechanistically, virus-induced lactate accumulation was associated with suppression of the retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway: excess lactate acted upstream of interferon regulatory factor 3 (IRF3), in a manner consistent with inhibition of the mitochondrial antiviral signaling protein (MAVS)-IRF3 axis, thereby attenuating type I interferon production. Together, these findings define a positive feedback loop in which RNA viruses exploit host metabolic reprogramming to accumulate lactate, which in turn restrains antiviral innate immunity and favors viral replication.IMPORTANCERNA viruses have no metabolism of their own and must rewire the host cell to replicate. Here, using two viruses from different families-Newcastle disease virus and influenza A virus-we show that infection rapidly drives host glucose uptake and glycolysis and causes lactate to accumulate. Lactate is not an inert by-product: blocking glycolysis lowers lactate, derepresses type I interferon and interferon-stimulated gene expression, and restricts viral replication, while adding lactate back reverses immune-signaling changes induced by glycolytic inhibition and further suppresses interferon regulatory factor 3 (IRF3) phosphorylation. Lactate therefore functions as an immunomodulatory effector linking virus-driven metabolic reprogramming to weakened innate immunity, consistent with inhibition of the mitochondrial antiviral signaling protein (MAVS)-IRF3 axis, forming a positive feedback loop that favoring replication. Since this loop was observed in two distinct RNA viruses, glycolysis and lactate handling may represent host-directed targets for antiviral intervention, while lactate's broader clinical relevance as an immune biomarker requires further investigation.