Reovirus induction of host inflammatory responses

项目概要 病毒性心肌炎是全世界发病和死亡的一个重要原因，特别是在儿童和儿童中 年轻人。尽管病毒性心肌炎具有临床重要性，但病毒引起心肌炎的机制 人们对心肌炎知之甚少。本申请中描述的实验的总体目标是定义 导致病毒性心肌炎发生的病毒和宿主决定因素。本文提出的工作 应用程序使用哺乳动物正呼肠孤病毒（呼肠孤病毒），这是研究病毒性心脏病的长期模型 新生儿感染。我们最近发现了一种强效心肌炎呼肠孤病毒株 (T1L/T3DM2) 对新生小鼠致命。我们的初步数据表明，T1L/T3DM2 的毒力明显减弱 在缺乏焦亡细胞死亡途径关键成分的小鼠中。在此应用程序中，我们将探讨如何 细胞焦亡会加剧呼肠孤病毒心肌炎。具体目标 1 中的实验将定义细胞焦亡的作用 呼肠孤病毒感染期间的心脏。具体目标 2 中的实验将定义呼肠孤病毒的机制 使用体内感染与原代心肌细胞的组合来诱导细胞焦亡。这个 研究将通过揭示控制免疫机制的广泛原则而产生广泛的影响 有助于病毒性心脏病。

PROJECT SUMMARY Viral myocarditis is a significant cause of morbidity and mortality worldwide, particularly in children and young adults. Despite the clinical importance of viral myocarditis, the mechanisms by which viruses cause myocarditis are poorly understood. The overall objective of experiments described in this application is to define viral and host determinants that contribute to the development of viral myocarditis. Work proposed in this application uses mammalian orthoreovirus (reovirus), which is a longstanding model for studying viral cardiac infections in neonates. We recently identified a potently myocarditic reovirus strain (T1L/T3DM2) that is highly lethal in neonatal mice. Our preliminary data indicate that the virulence of T1L/T3DM2 is markedly diminished in mice lacking key components of pyroptotic cell death pathway. In this application, we will explore how pyroptosis potentiates reovirus myocarditis. Experiments in Specific Aim 1 will define the role of pyroptosis in the heart during reovirus infection. Experiments in Specific Aim 2 will define mechanism by which reovirus induces pyroptosis using a combination in vivo infections in combination with primary cardiomyocytes. This research will have broad general impact by uncovering broad principles that govern immune mechanisms that contribute to viral cardiac disease.