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: 10644008
• 负责人: DeLisa Fairweather
• 金额: $ 74.21万
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644008
• 关键词: 2019-nCoV; Acute; Adult; Age; Animal Model; Autophagosome; Autopsy; Bioenergetics; Biogenesis; Biopsy; COVID-19 patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Communication; Cells; Child; Complex; Coxsackie Viruses; Data; Diagnosis; Dilated Cardiomyopathy; Disease; Disparate; Enterovirus; Estrogen Receptor alpha; Female; Goals; HIV; Heart; Heart Transplantation; Heart failure; Hepatitis C virus; Homeostasis; Human poliovirus; Immune response; Incidence; Infection; Inflammation; Inflammatory; Influenza A virus; Ingestion; Inner mitochondrial membrane; Lytic; Macrophage; Mediating; MicroRNAs; Mitochondria; Mitochondrial Proteins; Mus; Myelogenous; Myeloid Cells; Myocardial; Myocarditis; Myocardium; Outer Mitochondrial Membrane; Parkin; Patients; Phosphorylation; Proteins; Proteomics; Publishing; Reporting; Risk; Role; Severities; Sex Differences; Signal Transduction; Structure; Sudden Death; TLR4 gene; Time; Transcript; Tropism; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Woman; estrogenic; extracellular vesicles; heart damage; male; men; novel; response; sex; transcriptome sequencing

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.

项目摘要 据估计，2017年诊断出310万例心肌炎/心肌病。心肌炎患者 有因急性心力衰竭而猝死和发展为扩张型心肌病的风险， 需要进行心脏移植心肌炎的发病率和严重程度男性高于女性。 此外，没有疾病特异性疗法来减少心肌炎。肠道病毒包括 柯萨奇病毒B3组（CVB 3）是美国心肌炎的常见原因。病毒经常出现在 心肌炎患者的心肌内膜活检。目前尚不清楚为什么 肠道病毒如CVB 3将靶向心脏或机制如何相对温和的病毒感染如CVB 3 导致心力衰竭以前假设，压倒性的裂解性CVB 3感染损害了 心最近发表了CVB 3从心肌细胞中流出的主要模式是在心肌细胞中， 细胞外囊泡样线粒体自噬体，并且CVB 3需要线粒体分裂才能产生病毒 复制的有趣的是，其他引起心肌炎的病毒被发现利用线粒体来促进 病毒复制，包括甲型流感病毒、艾滋病毒、脊髓灰质炎病毒、丙型肝炎病毒和SARS-CoV-2。高能 心肌的需求和心脏中丰富的线粒体首次解释了 为什么这些不同类型的病毒，没有明显的心脏向性，在心脏中复制。的总目标 该建议是确定心肌细胞中通过线粒体的CVB 3复制周期是否诱导 心肌炎期间心脏炎症的性别差异，并确定是否microRNA和/或蛋白质 从尿道衍生的细胞外囊泡影响病毒复制和炎症的性别特异性 方式