Secondary cues alter ISG protein repertoires to unlock antiviral subprograms triggered by interferons

Abstract Immune defenses are triggered by cytokines like interferon-α (IFN-α) and IFN-γ in diverse cells. Both IFNs induce a class of factors termed IFN-stimulated genes (ISGs). Many ISG proteins have antiviral functions. There is a growing appreciation that ISG repertoires are cell-type specific and that this bias impacts infection outcomes. However, the cues and mechanisms driving these variable responses are ill-defined. Given key roles for immunometabolism in immune cell activation, we hypothesized that local cues like metabolites shape tissue specific ISG defenses. To model the impact of metabolic cues on host defenses in non-immune cells, we infected human cells with two unrelated viruses: vaccinia virus, the prototypical poxvirus, and herpes simplex virus-1 (HSV-1). Unexpectedly, we find that cells favoring glycolysis, but not OXPHOS, catalyze potent IFN-γ restriction of vaccinia and HSV-1 that attenuate viral-gene and protein expression as well as infectious virus production. This response is specific as modulating IFN-α signaling by supplementation with either glycolysis or OXPHOS cues has no effect on viral replication. This interferon-induced subprogram is independent of differences in canonical IFN-γ signal transduction, occurs at low levels of IFN-γ, and induced by physiological levels of glucose. RNA-seq reveals no marked changes in the “usual suspects” (e.g. ISGs). Instead, we find secondary cues regulate ISG protein levels. Deletion of a single ISG protein, which is differentially stabilized by secondary cues, is sufficient to rescue vaccinia replication. These data indicate that secondary cues can alter infection outcomes in the same cell-type by unlocking subprograms embedded in interferon catalyzed responses.