R01DK132735

Metabolic and Epigenetic Reprogramming of Vital Organs in SARS-CoV-2 Induced Systemic Toxicity - Project Summary/Abstract

SARS-CoV-2 primarily affects the respiratory system, but extra-pulmonary manifestations in individuals with COVID-19 are commonly seen. All major organ systems have been reported to be affected by SARS-CoV-2, and complications arising from ensuing organ dysfunction significantly increase the mortality rate of COVID-19. Yet, despite the clinical importance of systemic involvement of SARS-CoV-2, little is known about the pathogenesis of extra-pulmonary complications of COVID-19.

Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi-organ involvement and investigate the role of metabolic and epigenetic reprogramming of vital organs in the pathogenesis of systemic toxicity of COVID-19. We demonstrate that following a robust anti-viral immune response, there is metabolic suppression of oxidative phosphorylation and the tri-carboxylic acid (TCA) cycle in multiple organs. The animals develop a profound phenotype within 7 days of SARS-CoV-2 infection with severe weight loss, morbidity, and failure to thrive.

Examination of multiple internal organ systems demonstrated neutrophilia, lymphopenia, splenic atrophy, with cardiomyocyte cell death, myocardial edema, and extreme myofibrillar disarray observed in the heart, mirroring reported human clinical phenotypes in COVID-19. An organ-wide metabolic reprogramming consistent with depression of oxidative phosphorylation leads to utilization of peripheral fat stores and gross accumulation of fat in the heart, kidney, liver, and other vital organs.

We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation, several of these markers have been noted in human clinical studies to be associated with adverse prognosis. Finally, we demonstrate that despite the absence of viral genomes in tissues, transcriptional changes persist and are associated with significant differentially methylated regions in vital organs across the host cell genomes.

Considering these observations, we dissect the mechanistic basis of such metabolic reprogramming in SARS-CoV-2. We have created a multi-disciplinary team comprising metabolomics experts, virologists, physiologists, and geneticists to study metabolic fluxes and organ-wide transcriptomics to study in depth the role of metabolic and epigenetic reprogramming in causing SARS-CoV-2 induced severe systemic toxicity.

Los Angeles University Of California

NOT APPLICABLE

93.310 - Trans-NIH Research Support

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

California United States

State-Wide

NIH Directors Emergency Transformative Research Awards (R01 Clinical Trial Optional) (RFA-RM-20-020)

COVID-19 $2,378,661 (40%) percent of this Project Grant was funded by COVID-19 emergency acts including the CARES Act.
Amendment Since initial award the End Date has been extended from 08/31/24 to 08/31/25 and the total obligations have increased 65% from $3,636,473 to $6,015,134.