Role of viral mitophagosomes in driving sex differences in myocarditis

病毒线粒体吞噬体在心肌炎性别差异中的作用

• 批准号: 9892954
• 负责人: DeLisa Fairweather
• 金额: $ 12.24万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892954
• 关键词: Acute; Adult; Affect; Age; Animal Model; Automobile Driving; Autophagosome; Biopsy; Cardiac; Cardiac Myocytes; Cells; Child; Chloramphenicol; Chloroquine; Coxsackie Viruses; Diagnosis; Dilated Cardiomyopathy; Disease; Enterovirus; Genes; Goals; HIV; Heart; Heart Transplantation; Heart failure; Hepatitis C virus; Histology; Human poliovirus; Immune response; Incidence; Infection; Inflammation; Influenza A virus; Lytic; MicroRNAs; Mitochondria; Modeling; Mus; Myocardial; Myocarditis; Myocardium; Necrosis; Patients; Proteins; Publishing; Risk; Role; Severities; Sex Differences; Sudden Death; Time; Translations; Tropism; Vesicle; Viral; Viral Interference; Viral Proteins; Virus; Virus Diseases; Virus Replication; Virus Shedding; Woman; heart damage; male; men; microvesicles; novel; prevent; sex; transcriptome sequencing; viral myocarditis

PROJECT SUMMARY/ABSTRACT An estimated 1.5 million cases of myocarditis were diagnosed in 2015. 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 microvesicle-like mitochondrial autophagosomes, and that CVB3 requires mitochondria for viral replication. Interestingly, other viruses that cause myocarditis have been found to use mitochondria to promote viral replication including influenza A, HIV, poliovirus, and hepatitis C virus. 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 cardiac cells induces sex differences in cardiac inflammation during myocarditis and to determine whether microRNA from mitophagosomes reduce viral replication in mitochondria and thereby prevent heart failure during acute viral myocarditis.

项目概要/摘要 2015 年估计诊断出 150 万例心肌炎。心肌炎患者面临以下风险： 因急性心力衰竭而猝死并进展为扩张型心肌病，通常需要心脏手术 移植。男性心肌炎的发病率和严重程度高于女性。此外，没有 减少心肌炎的疾病特异性疗法。肠道病毒，包括柯萨奇病毒 B3 组 (CVB3) 在美国，这是心肌炎的常见原因。病毒经常在心内膜心肌活检中发现 心肌炎患者。目前尚不清楚为什么像 CVB3 这样的肠道病毒会 针对心脏或相对轻微的病毒感染（如 CVB3）如何导致心力衰竭的机制。 此前有人假设，压倒性的裂解性 CVB3 感染会损害心脏。这是最近 发表了CVB3病毒从心肌细胞流出的主要模式是微泡样 线粒体自噬体，并且 CVB3 需要线粒体来进行病毒复制。有趣的是，其他 已发现引起心肌炎的病毒利用线粒体来促进病毒复制，包括 甲型流感病毒、艾滋病毒、脊髓灰质炎病毒和丙型肝炎病毒。心肌的能量需求量大，且充沛 心脏中的线粒体首次解释了为什么存在如此不同类型的病毒 无明显向心性，在心脏复制。该提案的总体目标是确定是否 CVB3通过心肌细胞线粒体的复制周期诱导心脏炎症的性别差异 并确定来自线粒体吞噬体的 microRNA 是否会减少心肌炎期间的病毒复制 线粒体，从而预防急性病毒性心肌炎期间的心力衰竭。