Cellular Determinants of Coxsackievirus Myocarditis

描述（由申请人提供）：B组柯萨奇病毒（CVB）是感染性心肌炎的主要原因。虽然人们对肠道病毒的复制已经有了很好的了解，但我们对CVB发病机制的了解还不完整，而且主要是基于组织培养研究和小鼠模型的推断。病毒复制的组织特异性决定因素尚未得到广泛评估，但复制能力强但非心肌CVB变异的存在表明，可能存在限制或增强心肌细胞复制的因素。CVB心肌和非心肌变异致病潜力的差异已被定位于柯萨奇病毒基因组5'非翻译区发现的病毒内核糖体进入位点（IRES）。我们推测细胞蛋白和IRES之间的相互作用决定了柯萨奇病毒的心肌电位。如果这一假设是正确的，那么了解这些相互作用的本质可能会为治疗急性心肌炎或干预扩张型心肌病的发展提供新的治疗策略。因此，我们提出了实验方法来确定在原代心肌细胞中发现的与CVB的IRES相互作用的因子，并阐明它们在CVB复制中的功能意义。项目描述：我们建议进行实验，以全面鉴定心肌细胞（心肌细胞）内允许柯萨奇病毒感染和损伤心脏的蛋白质。这些实验将有助于我们了解病毒性心肌炎，并可能为这种危及生命的疾病带来新的治疗方法。

DESCRIPTION (provided by applicant): Group B coxsackieviruses (CVB) are a leading cause of infectious myocarditis. Although the replication of enteroviruses is generally well understood, our understanding of CVB pathogenesis is incomplete, and is largely based on inferences from tissue culture studies, and the use of murine models. Tissue specific determinants of viral replication have not been extensively evaluated, but the existence of replication competent but non-myocarditic CVB variants indicates that there are likely to be factors that restrict or augment replication in cardiac myocytes. This difference in the pathogenic potential of myocarditic and non-myocarditic variants of CVB has been mapped to viral internal ribosome entry site (IRES), found in the 5' untranslated region of the coxsackievirus genome. We speculate that interactions between cellular proteins and the IRES determine the myocarditic potential of coxsackieviruses. If this hypothesis is correct, understanding the nature of these interactions may suggest novel therapeutic strategies to treat acute myocarditis, or to interfere with the evolution of dilated cardiomyopathy. Consequently, we propose experimental approaches to identify factors found in primary cardiac myocytes that interact with the IRES of CVB, and to clarify their functional significance in CVB replication. Project Narrative: We propose experiments to comprehensively identify proteins within heart muscle cells (cardiac myocytes) that allow coxsackieviruses to infect and injure the heart. These experiments will aid our understanding of viral myocarditis and may lead to new therapies for this life-threatening illness.