Rewiring of mitochondrial metabolism invokes conserved subprograms of the interferon response to adapt antiviral defenses 

Mitochondria have emerged as key signaling platforms in host defense. Unclear aspects of OXPHOS may also tip infection outcomes; as evidenced by viral micropeptides, which interface with the respiratory chain, derived from host interferon (IFN)-regulated genes. To explore this, we infected interferon-primed cells grown with metabolites that induce a shift from mitochondrial OXPHOS and aerobic glycolysis. Using a model poxvirus, we found that human cells favoring glycolysis potently block viral replication when primed with IFN-g but not IFN-a or untreated. Yet, cells with increased mitochondrial activity showed no differences in viral replication for untreated and IFN-primed. The glycolytic/IFN-g response is broad acting as it also markedly restricts an unrelated DNA virus, HSV-1. We found that metabolic rewiring alters the combination of IFN-stimulated genes (ISG) at the protein but not RNA level across different cell types and species. Mechanistically, metabolites trigger selective protein degradation of some but not all induced ISGs. Deletion of a single ISG that is differentially stabilized by metabolic cues alleviates the block in viral replication. These conserved ISG subprograms regulated by a metabolic axis underscore the gravity of not only magnitude but also composition of early antiviral responses. In principle, these subprograms could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.