Role of viral mitophagosomes in driving sex differences in myocarditis

项目总结/摘要 据估计，2015年诊断出150万例心肌炎病例。心肌炎患者有 急性心力衰竭猝死和扩张型心肌病进展，通常需要心脏 移植心肌炎的发病率和严重程度男性高于女性。此外，没有 疾病特异性治疗，以减少心肌炎。包括柯萨奇病毒B3组（CVB 3）在内的肠道病毒是 在美国是心肌炎的常见病因病毒经常在子宫内膜活检中发现， 心肌炎患者。目前尚不清楚为什么像CVB 3这样的肠道病毒 靶向心脏或相对温和的病毒感染（如CVB 3）如何导致心力衰竭的机制。 以前假设，压倒性的溶解性CVB 3感染会损害心脏。最近有 发表了CVB 3从心肌细胞中流出的主要模式是微泡样的 线粒体自噬体，并且CVB 3需要线粒体进行病毒复制。有趣的是，其他 已经发现引起心肌炎的病毒利用线粒体来促进病毒复制， 甲型流感、HIV、脊髓灰质炎病毒和丙型肝炎病毒。心肌的高能量需求和丰富的 心脏中的线粒体首次解释了为什么这些不同类型的病毒， 无明显的心脏向性，在心脏内复制。本提案的总体目标是确定 心肌细胞线粒体内柯萨奇病毒B3复制周期诱导心肌炎症的性别差异 并确定来自线粒体吞噬体的microRNA是否能减少心肌炎中的病毒复制， 线粒体，从而预防急性病毒性心肌炎期间的心力衰竭。

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.