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

• 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
• 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

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.

项目总结/摘要 SARS-CoV-2主要影响呼吸系统，但在患有 COVID-19很常见。据报道，所有主要器官系统都受到SARS-CoV-2的影响 以及随后器官功能障碍引起的并发症显著增加了COVID-19的死亡率。 然而，尽管SARS-CoV-2全身性受累的临床重要性， COVID-19肺外并发症的发病机制。在这里，我们建立了SARS-CoV-2的小鼠模型， 诱导严重的全身毒性和多器官受累，并研究代谢和 在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 这表明，在强大的抗病毒免疫应答后，存在氧化代谢抑制， 磷酸化和三羧酸（TCA）循环在多个器官。动物们发展出一种深刻的 在SARS-CoV-2感染7天内出现严重的表型，伴有严重的体重减轻、发病率和茁壮成长失败。 多个内脏系统检查显示嗜中性粒细胞增多、淋巴细胞减少、脾萎缩， 在心脏中观察到心肌细胞死亡、心肌水肿和极端肌原纤维紊乱， 反映了COVID-19中报告的人类临床表型。器官范围的代谢重编程 与氧化磷酸化的抑制一致，导致外周脂肪储存的利用， 脂肪在心脏、肾脏、肝脏和其他重要器官中的积累。我们进行代谢组学分析 外周血和鉴定一组TCA循环代谢物，其用作抑制的氧化性代谢的生物标志物。 磷酸化，这些标志物中的几个在人类临床研究中被注意到与不良反应相关。 预后最后，我们证明，尽管组织中没有病毒基因组， 变化持续存在，并与整个生命器官中的显著差异甲基化区域相关。 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， 在SARS-CoV-2中的重编程。我们建立了一个多学科团队，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通量， 代谢和表观遗传重编程在导致SARS-CoV-2诱导严重 全身毒性