Project Summary To better understand the determinants of severe COVID19, we have focused on the inflammasome regulatory protein DPP9. GWAS have implicated DPP9 in poor outcomes in COVID19 and in the development of idiopathic pulmonary fibrosis. DPP9 and closely related DPP8 serve as endogenous inhibitors of the viral inflammasome sensors NLRP1 and CARD8. This pathway is activated by diverse mechanisms of pathogen sensing which include detection of viral encoded proteases, bacterial E3 ubiquitin ligases and direct sensing of viral dsRNA. Our preliminary data indicate that this pathway is transcriptionally upregulated in human myeloid cells in response to SARS-CoV-2, a stimulus which activates the inflammasome. We have also discovered that mice which lack Dpp8 and Dpp9 have dysregulated T cell responses and develop more severe disease when challenged with SARS-CoV-2. Our ongoing work seeks to better understand 1) the immunological differences conferred by the COVID19 risk allele rs2109069 “A” located within a DPP9 intronic region, 2) the basis for T cell dysregulation in our novel mouse model and 3) how T cell dysfunction influences disease severity in response to SARS-CoV-2 infection.