Supplement: Immunometabolic and epigenetic effects of obesity on innate immune surveillance in cancer

Project Summary: The COVID-19 pandemic has affected millions worldwide, however it is clear that there arepredisposing factors that lead to critical illness and mortality including older age, and underlyingconditions particularly type 2 diabetes (T2DM) and obesity. The Centers for Disease Control andPrevention (CDC) has reported that patients with T2DM may have up to ten-times greater risk of deathwhen they contract COVID-19. Understanding the immune response is critical to preventing or reducingmortality from COVID-19 and informing therapeutic strategies for this patient population. The overallaim of this proposal is to identify the immune basis for increased disease severity and death fromCOVID-19 in patients with obesity and T2DM.It is now appreciated that obesity is associated with immune dysregulation, which may be the cause ofsome obesity related diseases. For example, Natural killer (NK) cells, so-called due to their naturalcytotoxicity against viruses and tumors, are unable to kill targets efficiently in obese humans and mice.We have recently found similar defects in CD8 T cells in patients with obesity and T2DM. The keyunanswered questions are 1) are these immune defects responsible for the increased severity anddeath from COVID-19 in patients with obesity and T2DM 2) do patents with obesity and T2DM have anunderactive or overactive (damaging cytokine storm) in response to COVID-19? and 3) is metabolicdysregulation at the heart of these defects? It is critical to understand the immune basis for thissusceptibility in order to prevent or reduce mortality from COVID-19 and to inform therapeutic strategiesin this patient populations. Findings from this study may lead to understanding the immune responsein patients with obesity for future novel viral outbreaks.