PROJECT SUMMARY/ABSTRACT Unpredictability is the hallmark of Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a severe pediatric complication of SARS-CoV-2 infection. MIS-C is distinct from COVID-19. It is not associated with pre-existing cardiopulmonary, autoimmune, or hematologic disorders. It can occur either during acute phase with detectable SARS-CoV-2 virus, or in the post-infectious period of several weeks after acute infection. Milder symptoms of MIS-C include fevers, rashes, and gastrointestinal symptoms, but can progress to cytopenias, coagulopathy, myocardial dysfunction, coronary aneurysms, and/or shock. We and others have found that MIS- C is associated with pediatric overweight and obesity, thereby identifying over 380 million children at risk for this disease. The mechanisms by which overweight and obesity influence the development of MIS-C are unknown. Until a vaccine against SARS-CoV-2 is globally available to all children, they will remain vulnerable to MIS-C. Our preliminary studies indicate that MIS-C is a highly inflammatory disease that incites more severe immune cell activation than COVID-19, particularly in overweight and obese children. Overweight and obese children with MIS-C had more T cell lymphopenia and T cell activation than their normal weight counterparts, suggesting an increased risk for more severe disease. Deleterious genetic variants increasing IFN and inflammatory signaling were exclusively found in patients with MIS-C, rather than severe COVID-19. This is a mechanistic counterpoint to defective IFN signaling associated with severe COVID-19 in adults. Our central hypothesis is that pediatric overweight and obesity prime interferon signaling, thereby increasing T cell activation and ultimately, the risk of MIS-C Aim 1 will elucidate how pediatric overweight and obesity drive immune cell dysfunction during MIS-C. The proposed studies will test the hypotheses that pediatric overweight and obesity are associated with more severe MIS-C, characterized by excessive interferon signaling and T cell activation. Aim 2 will identify mechanistic risk factors for MIS-C. The proposed studies will test the hypothesis that, even in the absence of infection, circulating immune cells from overweight and obese children exhibit an increased interferon signature that promotes T cell activation. We will develop a strategy for stratifying MIS-C by integrating genetic screening with measures of body mass index. Building on collaborations spanning over a decade and unique cohorts of children with MIS-C and/or obesity, our investigator team brings expertise in MIS-C, host immunity, pediatric obesity and endocrinology, and multiomics. This project will generate causal insights of how overweight and obesity influence the development and severity of MIS-C, with the goal of developing strategies for a population that remains at risk for this disease.