Dysregulated glucose metabolism drives hyperinflammation and immune-mediated pathology during viral infection 4291

Abstract Description Successful host defense during viral infection requires tight control of inflammation to mount an effective immune response while limiting damage to the host. Loss of immune regulation can result in a cytokine storm leading to major immunopathology and serious disease consequences. Evidence has shown that the pathology of acute viral infections is not mediated by viral load, but rather this hyperinflammatory response. Cellular metabolism plays a key role in immune activation as immune cells have specific metabolic requirements that dictate their functional fate. Thus, metabolic processes can shape the intensity of the inflammatory response. Nevertheless, the mechanisms driving cytokine storm remain poorly understood. Here we investigated how metabolism in the local tissue environment regulates the inflammatory response to viral infection. We and others found that mice deficient in the type I IFN receptor (Ifnar-/-) are more susceptible to cytokine storm from influenza A virus (IAV) infection than wild-type (WT) mice, independent of viral load. We show that Ifnar-/- mice have a significantly altered lung metabolite profile during IAV infection, compared to WT mice. These early metabolic changes are associated with heightened glucose metabolism in immune cells, contributing to the development of immune-mediated pathology. Importantly, these results highlight the therapeutic potential of modulating immune metabolism to effectively treat cytokine storm. Funding Sources Supported by Canadian Institute of Health Research (CIHR) project grant and a CIHR Canada Graduate Scholarship - Master’s (CGS-M) Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)