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.
Highlights
SARS-CoV-2 is a respiratory pathogen, but it can cause significant issues in other organ systems [1]
We demonstrate a murine model of severe SARS-CoV-2 systemic toxicity that can be generated by first administering the human ACE2 (hACE2) transgene by associated virus serotype 9 (AAV-9) delivery, followed 2 weeks later with i.p. administration of SARS-CoV-2
Systemic viremia has been noted and implicated in multiorgan involvement in humans with COVID-19 [30], and this remains the primary reason we hypothesized that systemic injection of the virus would facilitate multiorgan seeding and systemic complications; this is the rationale for the i.p. delivery
Summary
SARS-CoV-2 is a respiratory pathogen, but it can cause significant issues in other organ systems [1]. Almost every organ system from the heart, brain, vasculature, hematopoietic, liver, skin, and others have been reported to be affected by COVID-19 and have resulted in complications such as acute cardiac dysfunction, thrombosis, immune dysfunction, and metabolic complications [2,3,4,5,6,7,8]. Clinical studies during this pandemic have demonstrated that, in individuals hospitalized with COVID-19, the presence of extrapulmonary organ involvement is a predictor of significantly increased morbidity and mortality [2, 4, 9]. The pathogenesis of extrapulmonary involvement and ensuing systemic toxicity in COVID-19 is largely unclear but remains paramount to our understanding of the disease presentation of COVID-19
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