31: Type I IFNs enhance metabolic activation to enable an antiviral response

Abstract

Type I IFNs induce an antiviral immune response within hours of virus infection, mediated by activation of signaling pathways downstream of the type I IFN receptor. An IFN-induced antiviral response requires both transcriptional activation of genes and the rapid translation of mRNAs into proteins that effect an antiviral response. Both these processes are energy taxing. Cognizant that IFNs activate both the PI3K-Akt/mTOR pathway that is associated with nutrient sensing, and AMPK, associated with stress-induced metabolic activation, we undertook studies to investigate whether IFN-alpha/beta treatment influences metabolic events to enable an antiviral response. Using a panel of mouse embryonic fibroblasts null for Akt1/2, p85s, AMPKa, TSC2 or 4E-BP1, i.e. with defects in various signaling intermediates along the PI3K/mTOR pathway, we provide evidence for IFN-induced regulation of glucose uptake, mediated by activation of the PI3K/mTOR pathway. Notably, we demonstrate that IFN regulation of glucose uptake is required for an antiviral response to infection with the cardiotropic virus, coxsackievirus B3 (CVB3). In addition, we provide evidence for IFN regulated increases in ATP production. In vivo, we provide evidence that activation of AMPK by the pharmacological agent metformin enhances the antiviral effects of IFN-s treatment in mice infected with CVB3, lending further support that metabolic activation enhances an IFN-induced antiviral response.