IMMUNOPATHIC MYOSITIS INDUCED BY PERSISTENT VIRUS

持续病毒引起的免疫病性肌炎

• 批准号: 2072371
• 负责人: RONALD P MESSNER
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2072371
• 关键词: Coxsackievirus; RNase protection assay; artificial immunosuppression; athymic mouse; autoimmune disorder; computer assisted sequence analysis; denervation; disease /disorder model; genetic regulation; genetic strain; host organism interaction; laboratory mouse; latent virus infection; molecular cloning; myositis; natural selections; tissue /cell culture; virus RNA; virus diseases

Enterovirus infection has been linked to the expression of several human autoimmune diseases including polymyositis, juvenile-onset diabetes, and cardiomyopathy. Evidence of prior enterovirus infection includes elevated antibody titers against virus and the detection of persistent viral RNA in the afflicted tissue. However, results from some studies are equivocal, and hence the role of enterovirus in precipitating autoimmune diseases is still unclear. Techniques for the detection of persistent enteroviruses are hampered by a lack of knowledge about the mechanism which underlies persistence. Similarly, the mariner in which persistent enterovirus provokes the induction or maintenance of immunologically-mediated tissue damage is not understood. This proposal employs a mouse model of coxsackievirus B 1-induced polymyositis to study mechanisms of virus persistence and evaluate the effect of virus persistence on immunopathic muscle disease. Two key attributes of this model are that viral RNA persists for long periods of time in muscle, and immunopathic disease is mediated by T cells. The first objective is to explore the nature of persistent virus and determine whether it is comprised of altered forms of viral RNA and/or infectious virus. Nuclease protection assays will be used to identify genomic deletions, sequence changes, and altered ratios of positive and negative RNA strands. Reactivation of infectious virus will be attempted with several different strategies including immunosuppression and muscle denervation. A somewhat unique strategy for virus reactivation will be to culture muscle in vitro where it is removed from potential anti-viral effects of the immune system. Tissues other than muscle that have previously been found to harbor persistent viral RNA will also be tested as potential reservoirs of virus. If infectious virus is recovered, it will be phenotypically and genotypically characterized and compared with the original infecting strain. The second objective seeks to better understand factors that influence the coevolution of host and virus, and focuses on selective pressures exerted by the host on development of virus persistence. Nude mice and inbred strains of mice with varying susceptibilities to myositis will be used to examine the influence of T cells and host background genes on the establishment of persistent infection. The third objective is to identify muscle genes that are differentially regulated as a result of virus persistence. The differential display technique will be used to analyze muscle for RNA transcripts that are upregulated or downregulated at different stages of the disease. Taken together, these experiments will clarify important interactions between persistent virus and the host that culminate in the development of immunopathic muscle disease. They will also lead to more effective approaches for the epidemiologic study of persistent virus- induced autoimmune disease.

肠病毒感染与几个人的表达有关 自身免疫性疾病，包括多聚肌炎，少年发作糖尿病和 心肌病。先前肠病毒感染的证据包括升高 针对病毒的抗体滴度和检测持续性病毒RNA 受苦的组织。但是，一些研究的结果是模棱两可的， 因此，肠病毒在沉淀自身免疫性疾病中的作用是 仍然不清楚。检测持续肠病毒的技术 由于缺乏对基础机制的知识所阻碍 持久性。同样，持久性肠病毒的水手 挑衅免疫学介导的组织的诱导或维持 损害不了解。该建议采用了鼠标模型 Coxsackievivirus B 1诱导的多聚肌炎研究病毒的机制 持久性并评估病毒持久性对免疫疗法的影响 肌肉疾病。该模型的两个关键属性是病毒RNA 肌肉中长时间持续存在，免疫性疾病是 由T细胞介导。第一个目标是探索 持续病毒并确定它是否由变化的形式组成 病毒RNA和/或传染性病毒。将使用核酸酶保护测定法 确定基因组缺失，序列变化和比率改变 正和负RNA链。感染病毒的重新激活将 尝试采用几种不同的策略，包括免疫抑制 和肌肉神经。病毒重新激活的一种独特的策略 将在体外培养肌肉，从而将其从潜力中清除 免疫系统的抗病毒作用。肌肉以外的组织 以前发现携带持续病毒RNA也将是 被测试为病毒的潜在储层。如果回收传染病， 它将在表型和基因型上进行表征和比较 与原始感染菌株。第二个目标试图更好 了解影响宿主和病毒共同进化的因素，以及 专注于宿主对病毒发育施加的选择性压力 持久性。裸鼠和近交菌株的小鼠菌株变化 对肌炎的敏感性将用于检查T的影响 细胞和宿主背景基因建立持久性 感染。第三个目标是识别肌肉基因 由于病毒持久性而受到差异调节。这 差分显示技术将用于分析RNA的肌肉 在不同阶段上调或下调的成绩单 疾病。综上所述，这些实验将澄清重要 持续病毒与宿主之间的相互作用 免疫性肌肉疾病的发展。他们还将导致更多 持续病毒流行病学研究的有效方法 诱发自身免疫性疾病。