An IFNg-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate anti-viral immune response

Viral infection makes us feel sick. The extent of these changes to our metabolism are relative to the severity of disease. Whether blood glucose levels are subject to infection-induced modulation is largely unknown. Here we show that strong, non-lethal infection restricts systemic glucose availability which promotes the antiviral IFN-I response. Following systemic viral infection of mice, we find that IFN? produced by ?d T cells directly stimulates pancreatic ß-cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens endogenous glucose output by the liver. Glucose restriction enhances type-I interferon production by curtailing lactate-mediated inhibition of IRF3 and NF-?B signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, which explains why patients with metabolic disease are more susceptible to viral infection. Overall design: To investigater the impact of cytokines on gene transcription in pancreatc beta cells, we FACS-purified these cells, after which we stimulated them with glucose in presence or absence of IFNg and IL-1b. We then performed gene expression analysis using data obtained from RNA-seq of 4 biolgical replicates under two different conditions Comparative gene expression profiling analysis of RNA-seq data for pancreatic beta cells stimulated with glucose in the presence (IFNg/IL1b) or absence (control) of IFNg and IL1b