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Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2–induced systemic toxicity
Shen Li, … , Vaithilingaraja Arumugaswami, Arjun Deb
Shen Li, … , Vaithilingaraja Arumugaswami, Arjun Deb
Published December 7, 2020
Citation Information: JCI Insight. 2021;6(2):e145027. https://doi.org/10.1172/jci.insight.145027.
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Research Article COVID-19 Metabolism

Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2–induced systemic toxicity

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Abstract

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.

Authors

Shen Li, Feiyang Ma, Tomohiro Yokota, Gustavo Garcia Jr., 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

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Figure 2

Involvement of major organ systems in a murine model of SARS-CoV-2–induced systemic toxicity.

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Involvement of major organ systems in a murine model of SARS-CoV-2–induc...
(A and B) Splenic weight (data shown as mean ± SEM; n = 10, eGFP; n = 14, hACE2; **P < 0.01, Student’s t test, 2 tailed) (A) and splenic cell counts of eGFP/SARS-CoV-2 and hACE2/SARS-CoV-2 animals (data shown as mean ± SEM; n = 5/group; *P < 0.05, **P < 0.01; Student’s t test, 2 tailed) (B). (C and D) B mode echocardiogram demonstrating thickness of heart walls (dotted lines) (C) and M mode echocardiogram demonstrating thickness and hyperdynamic contraction in diastole (green) and systole (yellow line) (D). (E and F) Ejection fraction and fractional shortening (E) and left ventricular internal diameter (LVID) in systole (s) and diastole (d) (F) (data shown as mean ± SEM; n = 5, eGFP; n = 9, hACE2; **P < 0.01, 2-way ANOVA with Sidak’s multiple comparisons analysis). (G) Thickness of the left ventricular anterior wall (LVAW) and posterior walls (LVPW) in systole (s) and diastole (d) between eGFP/SARS-CoV-2 and hACE2/SARS-CoV-2 animals (data shown as mean ± SEM, n = 5/eGFP, n = 9/hACE2, **P < 0.01, 2-way ANOVA with Sidak’s multiple comparisons analysis). (H–M) Transmission electron microscopy demonstrating cardiac muscle of eGFP/SARS-CoV-2 (H) hACE2/SARS-CoV-2 (I and J) animals showing parallel arrangement of myofibrils (red arrow) and mitochondria (black arrow) (H) and ‘ghost’ cell (I) with myocyte cell destruction (red arrow) (J) myofibrillar disarray with loss of parallel myofibrillar arrangement (red arrow) and (K) breaks in myofibrils seen with higher magnification (red arrow) (L and M). Transmission electron microscopy demonstrating myocyte to endothelial distance (yellow lines) in eGFP/SARS-CoV-2 (L) and hACE2/SARS-CoV-2 (M) heart, demonstrating wider intercellular gap. Scale bars: 5 μm (H–J) and 0.5 μm (K–M).

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