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