Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2-induced systemic toxicity.
Shen Li, Feiyang Ma, Tomohiro Yokota, Gustavo Garcia, Amelia Palermo, Yijie Wang, Colin Farrell, Yu-Chen Wang, Rimao Wu, Zhiqiang Zhou, Calvin Pan, Marco Morselli, Michael A Teitell, Sergey Ryazantsev, Gregory A Fishbein, Johanna Ten Hoeve, Valerie A Arboleda, Joshua Bloom, Barbara Dillon, Matteo Pellegrini, Aldons J Lusis, Thomas G Graeber, Vaithilingaraja Arumugaswami, Arjun Deb
Author Information
Shen Li: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Feiyang Ma: UCLA Cardiovascular Research Theme, David Geffen School of Medicine.
Tomohiro Yokota: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Gustavo Garcia: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine.
Amelia Palermo: California Nanosystems Institute.
Yijie Wang: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Colin Farrell: Department of Human Genetics, David Geffen School of Medicine.
Yu-Chen Wang: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Rimao Wu: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Zhiqiang Zhou: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Calvin Pan: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Marco Morselli: Department of Molecular, Cell and Developmental Biology, Division of Life Sciences.
Michael A Teitell: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine.
Sergey Ryazantsev: California Nanosystems Institute.
Gregory A Fishbein: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine.
Johanna Ten Hoeve: California Nanosystems Institute.
Valerie A Arboleda: Department of Human Genetics, David Geffen School of Medicine.
Joshua Bloom: Department of Human Genetics, David Geffen School of Medicine.
Barbara Dillon: Department of Environment, Health and Safety, UCLA, Los Angeles, California, USA.
Matteo Pellegrini: Department of Molecular, Cell and Developmental Biology, Division of Life Sciences.
Aldons J Lusis: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Thomas G Graeber: Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
Vaithilingaraja Arumugaswami: Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
Arjun Deb: Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
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.
