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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 2017 年估计诊断出 310 万例心肌炎/心肌病。心肌炎患者经常面临因急性心力衰竭而猝死并进展为扩张型心肌病的风险需要进行心脏移植。男性心肌炎的发病率和严重程度高于女性。此外，没有特定疾病的疗法可以减少心肌炎。肠道病毒包括柯萨奇病毒 B3 组 (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。目前尚不清楚为什么会出现这样的情况像 CVB3 这样的肠道病毒会以心脏为目标，或者像 CVB3 这样相对温和的病毒感染的机制导致心力衰竭。先前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，CVB3 从心肌细胞中病毒排出的主要模式是细胞外囊泡样线粒体自噬体，并且 CVB3 需要线粒体裂变来进行病毒传播复制。有趣的是，其他引起心肌炎的病毒也被发现利用线粒体来促进心肌炎的发生。病毒复制，包括甲型流感病毒、HIV、脊髓灰质炎病毒、丙型肝炎病毒和 SARS-CoV-2。高能量心肌和心脏中丰富的线粒体的需求首次提供了解释为什么这些不同类型的病毒没有明显的向心性，却在心脏中复制。总体目标为该提案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期间心脏炎症的性别差异，并确定 microRNA 和/或蛋白质是否存在来自线粒体来源的细胞外囊泡以性别特异性影响病毒复制和炎症方式。