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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 1

A murine model of SARS-CoV-2–induced systemic toxicity.

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A murine model of SARS-CoV-2–induced systemic toxicity.
(A) Temporal sch...
(A) Temporal schematic of injection of hACE2-AAV-9 or eGFP-AAV-9 and SARS-CoV-2 injection. (B) Huddled posture of hACE2/SARS-CoV-2 mice compared with eGFP/SARS-CoV-2 controls. (C) Body weight of mice measured daily over 7 days (data shown as mean ± SEM, n = 5/group, *P < 0.05, **P < 0.01, 2-way ANOVA with Sidak’s multiple comparisons analysis). (D) Food consumption measured by assessing daily food weight/cage. (E) ECG strip demonstrating slower heart rate in hACE2/SARS-CoV-2 mice (arrows point to ventricular beats). (F) Resting heart rates (data shown as mean ± SEM, n = 5/group, *P < 0.05, Student’s t test, 2 tailed) and (G) blood pressure measured by tail cuff in anesthetized mice (data shown as mean ± SEM, n = 5/eGFP, n = 2/hACE2; 3/5 of hACE2 group had unrecordable blood pressures, Student’s t test, 2 tailed). (H) Ventral view at necropsy demonstrating changes in s.c., gonadal, and omental fat in eGFP and hACE2 SARS-CoV-2 groups (black and unfilled arrows). (I) Weight of fat dissected from different regions in eGFP and hACE2 SARS-CoV-2 groups (data shown as mean ± SEM, n = 5/group, *P < 0.05, **P < 0.01, Student’s t test, 2 tailed).

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