Project 462594

Successful host defense requires tight control of inflammation to mount an effective immune response while limiting damage to the host. Loss of such inflammatory control can result in "cytokine storm" - a pathological dysregulated immune response characterized by immune cell hyperactivity and mass production of inflammatory proteins (cytokines) that causes tissue damage. Mortality from most acute viral infections, including Ebola, hemorrhagic fevers, seasonal influenza, and more recently SARS-CoV-2, is rarely due to the pathogen (virus) itself, but rather to such hyperinflammation by the host's immune system, causing organ damage and subsequent failure. While we know that the immune cells become hyperactive and produce excessive cytokines, we do not know what cause this dysregulation at the first place. A hallmark of any immune response is the profound change in energy requirement. As a result, cellular metabolism has emerged as a fundamental regulator in tuning the degree and type of immune function. The central question we will investigate in this proposal is how does metabolism in the local tissue environment regulate the fate of the inflammatory response to viral infection? To answer this, we will characterize the differences in nutrient dynamics and metabolism in the local tissue between a dysregulated vs. controlled inflammatory response to viral infection. Results from this study may provide better treatment to prevent or reduce tissue damage following viral infections