Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, 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 multiorgan 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 that there is metabolic suppression of oxidative phosphorylation and the tricarboxylic 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 performed metabolomic profiling of peripheral blood and identified a panel of TCA cycle metabolites that served as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, which 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.
【저자키워드】 COVID-19, epigenetics, metabolism, Intermediary metabolism, 【초록키워드】 SARS-CoV-2, Biomarker, Biomarkers, Pathogenesis, Toxicity, Peripheral blood, lymphopenia, human ACE2, electron microscopy, COVID-19 pathogenesis, animals, animal, Microscopy, morbidity, edema, immune response genes, phenotype, Manifestations, murine model, DNA methylation, mortality rate, heart rate, expression, metabolomic profiling, change, Epigenetic, metabolite, Multiorgan, administration, manifestation, Extrapulmonary, lethality, followed by, tricarboxylic acid, immune response gene, weight loss, failure to thrive, failure, multiple organs, multiple tissues, neutrophilia, pathogenic, complications of COVID-19, atrophy, transgene, TCA cycle, internal organs, significantly lower, Affect, oxidative phosphorylation, Myocardial, COVID-19 phenotypes, performed, develop, changes in, contribute, demonstrated, induce, much higher, expressing, internal organ, multiple organ, multiple tissue, 【제목키워드】 change, Epigenetic, metabolic, organ,