Role of viral mitophagosomes in driving sex differences in myocarditis

项目摘要/摘要 据估计，2015年诊断出150万例心肌炎。心肌炎患者有患心脏病的风险 急性心力衰竭猝死和发展为扩张型心肌病，通常需要心脏 移植。男性心肌炎的发病率和严重程度高于女性。此外，没有 针对疾病的治疗，以减少心肌炎。包括柯萨奇病毒B3组(CVB3)在内的肠道病毒 这是美国心肌炎的常见原因。病毒经常在心内膜心肌活检组织中发现 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。 以前的假设是，压倒性的裂解性CVB3感染会损害心脏。那是最近的事 报道称，CVB3病毒从心肌细胞中排出的主要方式是微囊泡样 线粒体自噬，以及CVB3需要线粒体进行病毒复制。有趣的是，其他 已发现引起心肌炎的病毒利用线粒体促进病毒复制，包括 甲型流感、艾滋病毒、脊髓灰质炎病毒和丙型肝炎病毒。心肌对能量的高需求和丰富 心脏中的线粒体首次为为什么这种不同类型的病毒提供了解释， 没有明显的心脏趋向性，在心脏内复制。这项提案的总体目标是确定是否 心肌细胞线粒体中CVB3复制周期在心脏炎症中的性别差异 在心肌炎期间，并确定来自有丝分裂噬菌体的microRNA是否减少了 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.