PROJECT SUMMARY This application is a supplement request to our P51 base grant to Tulane National Primate Research Center (TNPRC) to further the investigation of Post-Acute Sequelae of SARS-CoV-2 infection (PASC). This application proposes to investigate the overarching hypothesis that virus-induced gut dysfunction, microbial translocation and downstream interferon signaling induce dysregulation of metabolic pathways involved in glucose metabolism and the urea cycle in the liver, the latter functioning to remove toxic ammonia from the body. We hypothesize that these alterations contribute to major pathogenic features of CoVID-19 infection and PASC, particularly chronic fatigue, neurocognitive disturbances, and dysregulation of glucose utilization contributing to type 2 diabetes, which has increased prevalence in persons previously infected with SARS- CoV-2. Alterations in the urea cycle may also promote clotting disorders associated with severe SARS-CoV-2 infection. Predisposition to thrombus formation has been observed in persons with ornithine transcarbamylase deficiency, an enzyme within the urea cycle pathway converting ornithine to citrulline. Indeed, in our preliminary data, we present supportive evidence of reduced citrulline levels in severe CoVID-19 patients. This application leverages our ongoing studies PASC in the African green monkey providing all the necessary samples for this investigation. This application also takes advantage of the CoVID-19 NHP Coordinating Center at TNPRC where we and three other Centers are engaged in Long-CoVID studies and will deposit our data for further analysis. Addition therapeutic studies will be performed in hACE2 transgenic mice, K18, which our team has published on previously as a model for SARS-CoV-2 infection, utilizing nutritional supplements and compounds to restore metabolic function during infection. This application represents a novel inquiry into an exciting hypothesis that may provide new insights into novel and effective therapeutic strategies for SARS- CoV-2 infection and PASC.