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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 7

SARS-CoV-2–induced systemic toxicity is associated with decreased serum TCA cycle metabolites and DNA methylation changes in vital organs.

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SARS-CoV-2–induced systemic toxicity is associated with decreased serum ...
(A and B) LC/MS demonstrating significantly decreased (A) and significantly increased (B) metabolites in serum of hACE2/SARS-CoV-2 animals compared with control eGFP/SARS-CoV-2 animals (data shown as mean ± SEM, n = 5/group, **P < 0.01, Student’s t test, 2 tailed). (C) Downregulated TCA cycle genes in multiple organs (heart [H], lungs [L], kidney [K], spleen [S]) of hACE2/SARS-CoV-2 animals compared with eGFP/SARS-CoV-2 animals (*P < 0.05). Significantly downregulated genes are shown in blue font with accompanying log2 fold changes across multiple organs. Metabolites generated by enzymes encoded by affected genes are highlighted, and serum fold changes are shown in black circles. (D) Histogram showing the number of differentially methylated sites plotted as a distance from a differentially methylated site to the nearest transcription start site (TSS) (5kb bins) for both heart (median distance = 2424 bp) and kidney (median distance = 6390 bp) tissue (n = 3/group). (E) Percentage of CpG methylated sites spanning the first exon of Peg10 gene in hearts of hACE2/SARS-CoV-2 animals and associated change in gene expression (red) and eGFP/SARS-CoV-2 animals (black) (n = 3, q < 0.01). Sliding Linear Model method was used to estimate q values.

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