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.

项目摘要/摘要 SARS-COV-2主要影响呼吸系统，但患有 Covid-19通常是可见的。据报道，所有主要器官系统都受SARS-COV-2的影响 随之而来的器官功能障碍引起的并发症显着提高了COVID-19的死亡率。 然而，尽管SARS-COV-2的全身参与至少临床重要性，但对此知之甚少 COVID-19的肺外并发症的发病机理。在这里，我们创建了SARS-COV-2的鼠模型 诱导严重的全身毒性和多器官参与，并研究代谢和 重要器官在COVID-19的全身毒性的发病机理中的表观遗传重编程。我们 证明在强大的抗病毒免疫反应后，存在代谢抑制氧化。 多个器官中的磷酸化和三羧酸（TCA）循环。动物发展深刻 SARS-COV-2感染的7天内表型，体重减轻，发病率和未能繁殖。 对多个内部器官系统的检查表现出嗜中性粒细胞，淋巴细胞减少，脾萎缩，具有 心脏肌细胞死亡，心肌水肿和极端的肌原纤维混乱在心脏和 镜像在Covid-19中报告的人类临床表型。器官宽的代谢重编程 与氧化磷酸化的抑郁一致，导致外周脂肪储存和总体 脂肪在心脏，肾脏，肝脏和其他重要器官中的积累。我们执行代谢组分析 外周血并识别一组TCA循环代谢物，这些代谢物用作抑郁型氧化的生物标志物 磷酸化，在人类临床研究中注意到其中几种标记与不利有关 预后。最后，我们证明，尽管在组织中没有病毒基因组，但转录 变化持续存在，与跨整个重要器官的重要差异甲基化区域有关 宿主细胞基因组。考虑到这些观察，我们剖析了这种代谢的机械基础 在SARS-COV-2中重新编程。我们创建了一个由代谢组学专家组成的多学科团队， 病毒学家，生理学家和遗传学家研究代谢通量和器官广泛的转录组学以研究 代谢和表观遗传重编程在引起SARS-COV-2引起严重的深度 全身毒性。