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

JCI Insight. 2021 Jan 25;6(2):e145027. doi: 10.1172/jci.insight.145027.

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.

Keywords: COVID-19; Epigenetics; Intermediary metabolism; Metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Animals, Genetically Modified
  • COVID-19 / complications*
  • COVID-19 / metabolism
  • COVID-19 / physiopathology
  • COVID-19 / virology
  • Citric Acid Cycle / physiology
  • DNA Methylation / physiology
  • Disease Models, Animal
  • Epigenesis, Genetic / immunology*
  • Failure to Thrive / etiology*
  • Failure to Thrive / physiopathology
  • Humans
  • Immunity / genetics
  • Male
  • Mice
  • Oxidative Phosphorylation
  • Renin-Angiotensin System / physiology
  • SARS-CoV-2 / metabolism
  • SARS-CoV-2 / pathogenicity*
  • Wasting Syndrome / etiology*
  • Wasting Syndrome / physiopathology

Substances

  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2