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％的患有心肌炎或特发性膨胀心肌病的患者已显示出心肌的肠病毒RNA，很可能是由于B（CVB）组的Coxsackievieve造成的。对心肌炎的鼠模型的研究还表明，心脏自传性CVB3感染导致病毒RNA的持续性超出可以分离感染性病毒的时间。对这种持续基因组RNA形式的研究表明，肠病毒RNA具有基因组极端5'末端的缺失，这种形式的复制程度可能比野生型具有更有限的复制程度。这种持续的病毒可以在细胞培养中复制，并且可以通过，但不会产生在野生型病毒细胞培养中看到的经典细胞病变作用。该病毒群体显示出对野生型CVB的复制的干扰。该提议的假设是，已删除的coxsackievievirus是在心脏感染中产生的，从而限制了该病毒的复制和翻译并干扰剩余的野生型病毒，从而持续存在病毒。这种持续的病毒感染有助于肠胃病毒相关性心脏病的慢性炎症和心肌病。该提案的具体目的是分析我们检测到的五个已删除基因组的细胞培养中的复制，以及它们干扰野生型CVB的复制的能力，并在肠内病毒阳性人类心脏生物群中和来自不同CVB血清中感染的小鼠中的肠病毒阳性人心脏组织中的类似删除基因组进行分析。对这些缺陷基因组复制如何复制的仔细分析可能导致抗病毒治疗，该治疗可能提供了停止对心肌病的进展，并防止在这种激进治疗的四分之一的候选者中进行心脏移植的必要性。