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

• DOI: 10.1172/jci.insight.145027
• Publication Date: 2020-12-07T15:03:14Z
• Authors: 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 A...; Arjun Deb
• Keywords: Pathogenesis

Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, little is known about the pathogenesis systemic complications COVID-19. Here, we create murine model SARS-CoV-2–induced severe toxicity and multiorgan involvement by expressing human ACE2 transgene in multiple tissues via viral delivery, followed administration SARS-CoV-2. The animals develop profound phenotype within 7 days weight loss, morbidity, failure to thrive. We demonstrate that there metabolic suppression oxidative phosphorylation tricarboxylic acid (TCA) cycle organs neutrophilia, lymphopenia, splenic atrophy, mirroring phenotypes. Animals had significantly lower heart rate, electron microscopy demonstrated myofibrillar disarray myocardial edema, common pathogenic cardiac performed metabolomic profiling peripheral blood identified panel TCA metabolites served as biomarkers depressed phosphorylation. Finally, observed SARS-CoV-2 induces epigenetic changes DNA methylation, which affects expression immune response genes could, part, contribute pathogenesis. Our suggests reprogramming internal could lethality