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

SARS-CoV-2 引起的全身毒性中重要器官的代谢和表观遗传重编程

基本信息

批准号：
10272660
负责人：
Vaithilingaraja Arumugaswami
金额：
$ 363.65万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10272660
关键词：
2019-nCoV ACE2 Acute Adopted Advocate Aerobic Affect Animal Model Animals Antiviral Agents Antiviral Response Atrophic Biological Markers Body Weight decreased COVID-19 COVID-19 pathogenesis Cardiac Myocytes Cell Death Cell Line Cell Respiration Cell physiology Cells Cerebrovascular system Citric Acid Cycle Clinical Clinical Research Computational Biology DNA Methylation Data Defect Depressed mood Disease Down-Regulation Edema Electron Transport Epigenetic Process Epithelial Cells Exhibits Failure to Thrive Fatty acid glycerol esters Functional disorder Gene Expression Genetic Genetic Transcription Genome Genomics Heart Hematopoietic Histologic Human Immune System Diseases Immune response Individual Kidney Knowledge Lead Liver Lung Lymphopenia Mental Depression Metabolic Metabolic Pathway Metabolism Methylation Morbidity - disease rate Multiple Organ Failure Myocardial Myocardial dysfunction Neutrophilia Organ Oxidative Phosphorylation Pathogenesis Peripheral Phenotype Physiological Physiology Prognosis Reporting Research Respiratory System Role SARS-CoV-2 infection Site Skin Symptoms Systems Biology Thrombosis Tissues Viral Viral Genome Virus base body system clinical phenotype cytokine cytotoxicity disabling symptom epigenome epigenomics in vivo innovation insight metabolic abnormality assessment metabolomics mortality mouse model multidisciplinary novel novel therapeutic intervention pandemic disease peripheral blood receptor respiratory pathogen severe COVID-19 systemic toxicity trait transcriptomics

项目摘要

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.

项目概要/摘要 SARS-CoV-2 主要影响呼吸系统，但也会影响患有此病的个体的肺外表现 COVID-19 很常见。据报道，所有主要器官系统均受到 SARS-CoV-2 的影响以及随之而来的器官功能障碍引起的并发症显着增加了 COVID-19 的死亡率。然而，尽管 SARS-CoV-2 的全身性参与具有临床重要性，但人们对它的了解却知之甚少。 COVID-19 肺外并发症的发病机制。在这里，我们创建了 SARS-CoV-2 小鼠模型引起严重的全身毒性和多器官受累，并研究代谢和代谢的作用 COVID-19全身毒性发病机制中重要器官的表观遗传重编程。我们证明在强大的抗病毒免疫反应之后，氧化代谢受到抑制多个器官中的磷酸化和三羧酸（TCA）循环。动物们发展出深刻的 SARS-CoV-2 感染后 7 天内出现体重严重减轻、发病和生长迟缓的表型。多个内脏器官系统检查显示中性粒细胞增多、淋巴细胞减少、脾萎缩，在心脏和心脏中观察到心肌细胞死亡、心肌水肿和肌原纤维极度紊乱反映了报告的 COVID-19 人类临床表型。器官范围的代谢重编程与氧化磷酸化的抑制一致，导致外周脂肪储存和总脂肪的利用脂肪堆积在心、肾、肝等重要器官中。我们进行代谢组学分析外周血并鉴定一组 TCA 循环代谢物，作为氧化抑制的生物标志物磷酸化，在人类临床研究中注意到其中一些标记物与不良反应相关预后。最后，我们证明，尽管组织中不存在病毒基因组，转录变化持续存在，并与整个重要器官中显着差异的甲基化区域相关。宿主细胞基因组。考虑到这些观察结果，我们剖析了这种代谢的机制基础 SARs-CoV-2 中的重编程。我们创建了一个多学科团队，包括代谢组学专家、病毒学家、生理学家和遗传学家研究代谢流和器官范围的转录组学代谢和表观遗传重编程在引起 SARS-CoV-2 引起的严重后果中的作用的深度全身毒性。