IMMUNOPATHIC MYOSITIS INDUCED BY PERSISTENT VIRUS

持续病毒引起的免疫病性肌炎

• 批准号: 2072372
• 负责人: RONALD P MESSNER
• 金额: $ 19.18万
• 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/2072372
• 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.

肠道病毒感染与几种人类 自身免疫性疾病，包括多发性肌炎、青少年发病的糖尿病，以及 心肌病既往肠道病毒感染的证据包括 抗病毒抗体滴度和持续病毒RNA的检测 受损组织然而，一些研究的结果是模棱两可的， 因此肠道病毒在诱发自身免疫性疾病中的作用是 目前仍不清楚.持久性肠道病毒的检测技术 由于缺乏对这一机制的了解， 坚持不懈同样，在水手中， 引起免疫介导组织的诱导或维持 伤害不被理解。该提议采用了小鼠模型， 柯萨奇病毒B 1诱导的多发性肌炎研究病毒机制 持久性和评估病毒持久性对免疫性疾病的影响 肌肉疾病该模型的两个关键属性是， 在肌肉中持续很长一段时间，免疫性疾病是 由T细胞介导。第一个目标是探讨 持续存在的病毒，并确定它是否由改变形式的 病毒RNA和/或感染性病毒。将使用核酸酶保护试验 以确定基因组缺失、序列变化和 正和负RNA链。感染性病毒的重新激活将 可以尝试几种不同的策略，包括免疫抑制 和肌肉去神经。一种独特的病毒再激活策略 将在体外培养肌肉， 免疫系统的抗病毒作用。肌肉以外的组织， 此前被发现携带持久性病毒RNA的人也将被发现 被检测为潜在的病毒宿主如果发现感染性病毒， 它将被表型和基因型表征和比较， 与最初的感染菌株第二个目标是更好地 了解影响宿主和病毒共同进化的因素， 着重于宿主对病毒发展施加的选择性压力 坚持不懈裸鼠和近交系小鼠具有不同的 对肌炎的易感性将被用来检查T 细胞和宿主背景基因对建立持久性 感染第三个目标是确定肌肉基因， 由于病毒持续存在而受到不同的调节。的 差异显示技术将用于分析肌肉的RNA 转录本在不同阶段上调或下调， 这种疾病综合起来，这些实验将阐明重要的 持续存在的病毒和宿主之间的相互作用， 免疫性肌肉疾病的发展。它们也将导致更多的 持续性病毒流行病学研究的有效方法- 诱发自身免疫性疾病