Extra-pulmonary manifestations of COVID-19 are associated with a much higher mortality rate. Yet, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi-organ involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity and failure to thrive. We demonstrate there is metabolic suppression of oxidative phosphorylation and the tri-carboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia and splenic atrophy mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, that affects expression of immune response genes and could in part contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2 induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.
Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2 induced systemic toxicity / Li, S; Ma, F; Yokota, T; Garcia, G Jr; Palermo, A; Wang, Y; Farrell, C; Wang, Yc; Wu, R; Zhou, Z; Pan, C; Morselli, M; Teitell, Ma; Ryazantsev, S; Fishbein, Ga; Ten Hoeve, J; Arboleda, Va; Bloom, J; Dillon, Bj; Pellegrini, M; Lusis, Aj; Graeber, Tg; Arumugaswami, V; Deb, A. - In: JCI INSIGHT. - ISSN 2379-3708. - (2021). [10.1172/jci.insight.145027]
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