Cellular Determinants of Coxsackievirus Myocarditis

描述（由申请方提供）：B组柯萨奇病毒（CVB）是感染性心肌炎的主要原因。虽然肠道病毒的复制通常是很好的理解，我们的理解CVB发病机制是不完整的，主要是基于组织培养研究的推论，并使用小鼠模型。尚未对病毒复制的组织特异性决定因素进行广泛评价，但存在复制能力但非心肌性CVB变异体表明可能存在限制或增强心肌细胞复制的因素。CVB的心肌炎性和非心肌炎性变体的致病潜力的这种差异已经被定位到病毒内部核糖体进入位点（IRES），其在柯萨奇病毒基因组的5'非翻译区中发现。我们推测细胞蛋白质和IRES之间的相互作用决定了柯萨奇病毒的心肌炎潜力。如果这一假设是正确的，了解这些相互作用的性质可能会提出新的治疗策略来治疗急性心肌炎，或干预扩张型心肌病的演变。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，并阐明其在CVB复制中的功能意义。项目叙述：我们提出的实验，以全面确定心肌细胞（心肌细胞）内的蛋白质，使柯萨奇病毒感染和损伤的心脏。这些实验将有助于我们了解病毒性心肌炎，并可能导致这种危及生命的疾病的新疗法。

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.