Project Summary/Abstract SARS-CoV-2 primarily affects the respiratory system but extra-pulmonary manifestations in individuals with COVID-19 are commonly seen. All major organ systems have been reported to be affected by SARS-CoV-2 and complications arising from ensuing organ dysfunction significantly increase the mortality rate of COVID-19. Yet, despite the clinical importance of systemic involvement of SARS-CoV-2, little is known about the pathogenesis of extra-pulmonary complications of COVID-19. Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi-organ involvement and investigate the role of metabolic and epigenetic reprogramming of vital organs in the pathogenesis of systemic toxicity of COVID-19. We demonstrate that following a robust anti-viral immune response, there is metabolic suppression of oxidative phosphorylation and the tri-carboxylic acid (TCA) cycle in multiple organs. The animals develop a profound phenotype within 7 days of SARS-CoV-2 infection with severe weight loss, morbidity and failure to thrive. Examination of multiple internal organ systems demonstrated neutrophilia, lymphopenia, splenic atrophy, with cardiomyocyte cell death, myocardial edema and extreme myofibrillar disarray observed in the heart and mirroring reported human clinical phenotypes in COVID-19. An organ wide metabolic reprogramming consistent with depression of oxidative phosphorylation leads to utilization of peripheral fat stores and gross accumulation of fat in the heart, kidney, liver and other vital organs. We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation, several of these markers been noted in human clinical studies to be associated with adverse prognosis. Finally, we demonstrate that despite the absence of viral genomes in tissues, transcriptional changes persist and are associated with significant differentially methylated regions in vital organs across the host cell genomes. Considering these observations, we dissect the mechanistic basis of such metabolic reprogramming in SARs-CoV-2. We have created a multi-disciplinary team comprising, metabolomics experts, virologists, physiologists and geneticists to study metabolic fluxes and organ wide transcriptomics to study in the depth the role of metabolic and epigenetic reprogramming in causing SARS-CoV-2 induced severe systemic toxicity.