Role of mitochondrial extracellular vesicles in CVB3 myocarditis by sex

线粒体细胞外囊泡在不同性别的 CVB3 心肌炎中的作用

• 批准号: 10852725
• 负责人: DeLisa Fairweather
• 金额: $ 2.44万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852725
• 关键词: 2019-nCoV; Acute; Autophagosome; Biopsy; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Coxsackie Viruses; Diagnosis; Dilated Cardiomyopathy; Disease; Disparate; Enterovirus; Goals; HIV; Heart; Heart Transplantation; Heart failure; Hepatitis C virus; Human poliovirus; Incidence; Infection; Inflammation; Influenza A virus; Lytic; MicroRNAs; Mitochondria; Mitochondrial Proteins; Myocardial; Myocarditis; Myocardium; Patients; Publishing; Risk; Role; Severities; Sex Differences; Sudden Death; Time; Travel; Tropism; Viral; Virus; Virus Diseases; Virus Replication; Wages; Woman; extracellular vesicles; heart damage; men; sex; undergraduate student

PROJECT SUMMARY An estimated 3.1 million cases of myocarditis/cardiomyopathy were diagnosed in 2017. Patients with myocarditis are at risk of sudden death from acute heart failure and progression to dilated cardiomyopathy, often necessitating a heart transplant. The incidence and severity of myocarditis is higher in men than women. Additionally, there are no disease-specific therapies to reduce myocarditis. Enteroviruses including coxsackievirus group B3 (CVB3) are a common cause of myocarditis in the US. Viruses are frequently found in endomyocardial biopsies from patients with myocarditis. There is currently no clear understanding of why an enterovirus like CVB3 would target the heart or the mechanism for how a relatively mild viral infection like CVB3 leads to heart failure. Previously it was hypothesized that an overwhelming lytic CVB3 infection damages the heart. It was recently published that the predominant mode of viral egress for CVB3 from cardiomyocytes is in extracellular vesicle-like mitochondrial autophagosomes, and that CVB3 requires mitochondrial fission for viral replication. Interestingly, other viruses that cause myocarditis have been found to use mitochondria to promote viral replication including influenza A, HIV, poliovirus, hepatitis C virus and SARS-CoV-2. The high energy demands of cardiac muscle and abundant mitochondria in the heart provide for the first time an explanation for why such disparate types of viruses, with no obvious cardiac tropism, replicate in the heart. The overall goal of this proposal is to determine whether the CVB3 replicative cycle through mitochondria in cardiomyocytes induces sex differences in cardiac inflammation during myocarditis and to determine whether microRNA and/or protein from mitochondrial-derived extracellular vesicles influence viral replication and inflammation in a sex-specific manner. The specific goal of this diversity supplement is to provide salary and travel for an undergraduate student.

项目总结 据估计，2017年诊断出310万例心肌炎/心肌病。心肌炎患者 有可能因急性心力衰竭而猝死，并进展为扩张型心肌病，通常 需要进行心脏移植。男性心肌炎的发病率和严重程度高于女性。 此外，目前还没有针对疾病的治疗方法来减少心肌炎。肠道病毒包括 柯萨奇B3病毒群(CVB3)是美国心肌炎的常见原因。病毒经常出现在 心肌炎患者的心内膜心肌活检。目前还没有明确的理解为什么 像CVB3这样的肠道病毒会以心脏为靶标，或者像CVB3这样相对轻微的病毒感染的机制 会导致心力衰竭。此前，人们假设压倒性的裂解性CVB3感染会损害 心。最近发表的研究表明，病毒从心肌细胞中排出的主要方式是 细胞外囊泡样线粒体自噬小体，CVB3病毒需要线粒体分裂才能感染病毒 复制。有趣的是，其他导致心肌炎的病毒已被发现利用线粒体促进 病毒复制包括甲型流感、艾滋病毒、脊髓灰质炎病毒、丙型肝炎病毒和SARS-CoV-2。高能 对心肌的需求和心脏中丰富的线粒体首次为 为什么如此不同类型的病毒，没有明显的心脏趋向性，在心脏中复制。的总目标是 该建议旨在确定心肌细胞中通过线粒体的CVB3复制周期是否诱导 心肌炎时心脏炎症的性别差异及确定microRNA和/或蛋白 线粒体来源的胞外小泡影响性别特异的病毒复制和炎症 举止。这一多样化补充的具体目标是为本科生提供工资和旅行 学生。