Mitochondrial dysfunction enhances influenza pathogenesis by upregulating sialic acid biosynthesis
Viral infections are well-established triggers of disease progression in pediatric mitochondrial disease (MtD). Caregivers frequently report that these infections are not only more severe but also prolonged, a concern reflected in high adherence to infection prevention practices within the MtD community. Despite these observations, significant gaps remain in our understanding of host-pathogen interactions during viral infections in MtD. We hypothesized that mitochondrial dysfunction in MtD exacerbates viral pathogenesis and morbidity through metabolic allostatic alterations in infected cells. Using the Ndufs4 knock out (KO) mouse model of MtD, we observed severe clinical outcomes following influenza A virus infection, including pronounced weight loss, elevated viral load, cytokine storm, and reduced post-infection survival. Metabolic profiling in Ndufs4 KO lung epithelial cells (LET1), indicated a shift towards glycolysis and suggested a diversion of glucose carbons into anabolic pathways. Based on this finding, we determined that the increased influenza-associated susceptibility and morbidity in Ndufs4 KO was related to elevated levels of sialic acid (SIA), a key influenza receptor, derived from glycolysis. Pharmacological manipulation of glycolysis reduced SIA levels, viral load, and morbidity in Ndufs4 KO mice. Our findings demonstrate that metabolic dysregulation in MtD exacerbates viral attachment and pathogenesis, contributing to worsened clinical outcomes. Overall design: We conducted RNAseq analysis of (1) influenza A virus (IAV)-infected mouse lung RNA extracts (5 x WT and 5 x Ndufs4 KO), (2) IAV-infected mouse lung epithelial type I (LET1) cell RNA extracts (5 x WT and 4 x Ndufs4 KO), and (3) uninfected mouse lung epithelial type I (LET1) cell RNA extracts (5 x WT and 5 x Ndufs4 KO).