Enterovirus persistence in myocarditis

肠道病毒在心肌炎中持续存在

• 批准号: 6660720
• 负责人: Nora M. Chapman
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-17 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660720
• 关键词: Coxsackievirus; HeLa cells; clinical research; complementary DNA; gene deletion mutation; human genetic material tag; laboratory mouse; molecular cloning; myocarditis; pathologic process; transfection; virulence; virus RNA; virus genetics; virus replication

DESCRIPTION (provided by applicant): 20-40% of patients diagnosed with myocarditis or idiopathic dilated cardiomyopathy have been shown to have enteroviral RNA in their heart muscle, most likely resulting from infection with a coxsackievirus of the B (CVB) group. Studies of the murine model for myocarditis has also indicated that infection with cardiovirulent CVB3 results in persistence of viral RNA beyond the time at which infectious virus can be isolated. An investigation into the form of this persisting genomic RNA demonstrated that the enteroviral RNA has deletions of the extreme 5' end of the genome, a form which may have a more limited extent of replication than the wild type. This persisting virus can replicate in cell culture and can be passed but does not generate the classic cytopathic effect seen in cell culture of the wild type virus. This virus population displays interference with the replication of wild type CVBs. The hypothesis of this proposal is that deleted coxsackieviruses are generated in infection of the heart that limit replication and translation of this virus and interfere with remaining wild type virus so that virus persists. This persisting viral infection contributes to chronic inflammation and cardiomyopathy in later stage enterovirus-related inflammatory heart disease. The specific aims of this proposal are to analyze the replication in cell culture of five deleted genomes that we have detected, and their ability to interfere with replication of wild type CVBs and to assay for similar deleted genomes in enterovirus-positive human heart biopsies and in murine heart tissue from mice infected with different CVB serotypes. The careful analysis of how these defective genomes replicate is likely to lead to an antiviral treatment which may provide means of halting the progression to cardiomyopathy and preventing the necessity for heart transplantation in perhaps a quarter of candidates for this radical treatment.

描述（由申请人提供）：20-40%诊断为心肌炎或特发性扩张型心肌病的患者的心肌中显示有肠道病毒RNA，最可能是由B组柯萨奇病毒（CVB）感染引起的。对小鼠心肌炎模型的研究也表明，心脏毒性CVB 3感染导致病毒RNA的持续存在超过了感染性病毒可以分离的时间。对这种持续存在的基因组RNA形式的研究表明，肠道病毒RNA具有基因组末端5'端的缺失，这种形式可能具有比野生型更有限的复制程度。这种持续存在的病毒可以在细胞培养物中复制，并且可以传代，但不会产生在野生型病毒的细胞培养物中观察到的经典细胞病变效应。该病毒群体显示出对野生型CVB复制的干扰。该提议的假设是，在心脏感染中产生缺失的柯萨奇病毒，其限制该病毒的复制和翻译，并干扰剩余的野生型病毒，使得病毒持续存在。这种持续的病毒感染有助于慢性炎症和心肌病在后期阶段肠道病毒相关的炎症性心脏病。本提案的具体目的是分析我们检测到的五个缺失基因组在细胞培养中的复制，以及它们干扰野生型CVB复制的能力，并测定肠道病毒阳性的人心脏活检和感染不同CVB血清型的小鼠心脏组织中相似的缺失基因组。对这些缺陷基因组如何复制的仔细分析可能会导致抗病毒治疗，这可能会提供阻止心肌病进展的方法，并防止可能有四分之一的候选人接受心脏移植。