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Principal Investigator: Vaithilingaraja Arumugaswami
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2021
Award: $3,636,473
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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 and
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 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
the depth the role of metabolic and epigenetic reprogramming in causing SARS-CoV-2 induced severe
systemic toxicity.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Abnormal Assessment of Metabolism><Acute><Adopted><Advocate><Aerobic><Affect><Animal Model><Animal Models and Related Studies><Animals><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Atrophic><Atrophy><Biological Markers><Body Tissues><Body Weight decreased><COVID-19><COVID-19 infection><COVID-19 pathogenesis><COVID-19 virus><COVID19><COVID19 infection><COVID19 pathogenesis><COVID19 virus><CV-19><CV19><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Death><Cell Function><Cell Line><Cell Process><Cell Respiration><Cell physiology><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Respiration><Cerebrovascular system><Citric Acid Cycle><Clinical><Clinical Research><Clinical Study><CoV-2><CoV2><Computational Biology><DNA Methylation><Data><Defect><Depressed mood><Disease><Disorder><Down-Regulation><Downregulation><Dropsy><Dysfunction><Edema><Electron Transport><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Exhibits><Failure to Thrive><Fats><Fatty acid glycerol esters><Functional disorder><Gene Expression><Gene Transcription><Genetic><Genetic Transcription><Genome><Genomics><Heart><Heart Muscle Cells><Heart myocyte><Hematopoietic><Histologic><Histologically><Human><Hydrops><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Individual><Intermediary Metabolism><Kidney><Kidney Urinary System><Knowledge><Krebs Cycle><Lead><Liver><Lung><Lung Respiratory System><Lymphocytopenia><Lymphopenia><Lytotoxicity><MOF syndrome><Mental Depression><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Methylation><Modern Man><Morbidity><Morbidity - disease rate><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Myocardial><Myocardial depression><Myocardial dysfunction><Neutrophilia><Organ><Organ System><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Pathogenesis><Pb element><Peripheral><Phenotype><Physiologic><Physiological><Physiology><Physiopathology><Prognosis><Pulmonary Body System><Pulmonary Organ System><RNA Expression><Receptor Protein><Reporting><Research><Respiratory System><Respiratory Tracts><Respiratory tract structure><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Site><Skin><Strains Cell Lines><Subcellular Process><Symptoms><Systems Biology><TCA cycle><Thrombosis><Tissues><Transcription><Tricarboxylic Acid Cycle><Viral><Viral Genome><Virus><Weight Loss><Weight Reduction><Wuhan coronavirus><aerobic metabolism><aerobic respiration><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral drugs><anti-virals><base><bio-markers><biologic marker><biomarker><body system><body weight loss><brain blood vessels><brain vasculature><cardiac dysfunction><cardiomyocyte><cerebral blood vessel><cerebral vasculature><cerebrovascular vessels><cerebrovasculature><clinical phenotype><computer biology><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 virus><cultured cell line><cytokine><cytotoxicity><debilitating symptom><depressed><depression><disabling symptom><electron transfer><epigenome><epigenomics><hCoV19><heart dysfunction><heavy metal Pb><heavy metal lead><hemopoietic><hepatic body system><hepatic organ system><host response><immune system response><immunoresponse><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><insight><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung pathogen><metabolic abnormality assessment><metabolism measurement><metabolomics><metabonomics><model of animal><model organism><mortality><mouse model><multidisciplinary><multiorgan failure><multiple organ system failure><murine model><nCoV2><necrocytosis><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oxidative metabolism><pandemic><pandemic disease><pathophysiology><peripheral blood><pulmonary><pulmonary pathogen><receptor><renal><respiratory pathogen><sadness><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><systemic toxicity><thrombotic disease><thrombotic disorder><trait><transcriptomics><virus genome><wt-loss>