Abstract As the COVID-19 pandemic was considered to have a limited impact in children, a severe multi-inflammatory syndrome that specifically affects children (MIS-C) has recently emerged. MIS-C phenotypes include a combination of typical/atypical Kawasaki disease (KD) and toxic shock syndrome. Unlike adults with COVID-19, however, most children display gastrointestinal symptoms but fail to present significant respiratory involvement. A subset of patients develops coronary artery aneurysms, as seen in KD. Importantly, while a large body of studies on adult responses to SARS-CoV-2 is being reported, knowledge gaps about the immune responses to SARS-CoV-2 in children remain disproportionally large. We hypothesize that a comprehensive systems analysis approach that incorporates high-resolution immunologic assays is required to efficiently identify the most relevant immune factors that contribute to the pathogenesis of COVID-19 related-MIS-C and to determine its subsequent outcomes. For these reasons, we have assembled an experienced multidisciplinary team to study COVID-19 related MIS-C. We will leverage expertise in pediatric clinical research together with application of high-resolution multi-omics and analytical tools to characterize the immune system dysregulation underlying MIS-C. Towards this end, we will examine longitudinal samples and will compare the results with those of matched healthy controls with and without previous exposure to SARS-CoV-2. This study offers a unique opportunity to carefully dissect the contributions of the different components of the immune system to the most severe form of SARS-CoV- 2 responses in children. Our specific Aims are 1) to define the clinical variables and risk factors associated with MIS-C and establish a longitudinal sample biorepository, 2) to identify innate immunity parameters associated with SARS-CoV-2 infection-related MIS-C, and 3) to characterize specific anti-SARS-CoV2 adaptive immune responses in patients with MIS-C. This proposal will address major knowledge gaps in MIS-C pathogenesis in children. Completion of the project goals will lead to better understanding of dysregulated immune pathways and to the identification of novel biomarkers and therapeutic targets for this new syndrome.