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

项目摘要/摘要 SARS-CoV-2主要影响呼吸系统，但患者的肺外表现 新冠肺炎是常见的。据报道，所有主要器官系统都受到了SARS-CoV-2的影响。 随之而来的器官功能障碍引起的并发症显著增加了新冠肺炎的死亡率。 然而，尽管SARS-CoV-2全身性感染具有重要的临床意义，但人们对 新冠肺炎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，并调查代谢和 新冠肺炎全身毒性发病机制中重要器官的表观遗传学重编程。我们 证明在强大的抗病毒免疫反应之后，存在氧化代谢抑制 多器官的磷酸化和三羧酸(TCA)循环。这些动物发展出了一种深刻的 在感染SARS-CoV-2的7天内表现出严重的体重减轻、发病率和无法茁壮成长。 多脏器系统检查显示中性粒细胞减少，淋巴细胞减少，脾萎缩， 在心脏和心脏观察到心肌细胞死亡、心肌水肿和极端的肌原纤维紊乱 反映了新冠肺炎上报告的人类临床表型。一种全器官的代谢重编程 与氧化磷酸化抑制一致导致外周脂肪储备和粗大脂肪的利用 脂肪积聚在心脏、肾脏、肝脏等重要器官。我们进行新陈代谢图谱分析 并确定一组作为氧化抑制生物标志物的TCA循环代谢物 这些标志物中的几个在人类临床研究中被发现与不良反应有关 预后。最后，我们证明，尽管组织中没有病毒基因组，但转录的 变化持续存在，并与重要器官中显著差异的甲基化区域有关 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制基础。 SARS-CoV-2中的重新编程。我们已经建立了一个多学科的团队，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全基因转录研究 代谢和表观遗传重编程在SARS-CoV-2诱导的重症中的作用 全身毒性。

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.