IMMUNOPATHIC MYOSITIS INDUCED BY PERSISTENT VIRUS

持续病毒引起的免疫病性肌炎

• 批准号: 2901587
• 负责人: RONALD P MESSNER
• 金额: $ 23.96万
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2901587
• 关键词: Coxsackievirus; autoimmune disorder; autoimmunity; chronic disease /disorder; computer assisted sequence analysis; disease /disorder etiology; genetic strain; genome; host organism interaction; immunopathology; inflammation; laboratory mouse; myositis; nucleic acid sequence; virus genetics

Prior enterovirus infection has been implicated in pathogenesis of certain human autoimmune diseases including the idiopathic inflammatory myopathies, juvenile-onset diabetes, and cardiomyopathy, as well as noninflammatory diseases like chronic fatigue syndrome. How the elements of enteroviral infection are linked to development of post-viral disease is unclear, but the process is probably driven by factors inherent in viral and host genomes and possibly by interaction of these factors with other environmental stimuli. This proposal is focused on identifying the specific viral gene or genes that are crucial to disease induction in a well-characterized mouse model of chronic inflammatory myopathy (CIM). CIM is induced in susceptible mouse strains by neonatal infection with coxsackievirus B1 (CVB1). A panel of CVB1 variants has been produced that are myopathic (MP) or amyopathic (AMP) with respect to CIM induction and which will be used to identify the viral components that mediate CIM development. First, infectious cDNA clones from both a prototypic MP and an AMP variant will be produced. Pathogenic phenotypes of the cloned viruses will be tested in vivo to confirm that they are equivalent to the parental viruses. The two prototypic viral clones will then be sequenced to identify specific genomic differences and construct a map of putative myopathogenicity-inducing regions. Next, the functional significance of these differences will be tested by creating MP/AMP chimeras from the clones and evaluating CIM induction using a panel of five pathologic indicators. In vivo infection with reciprocal chimeras will confirm which genomic regions are coupled to CIM development. The effect of specific genetic differences will then be verified at the single nucleotide level. Myopathic regions in the remaining variants will be examined to determine if amyopathic changes in the AMP prototype are conserved or if different mutations have occurred which have the same functional effect. This will also reveal whether the dominant disease determinants have been mapped or if additional viral genes are involved. MP3, a unique variant that induces weakness in the absence of inflammation, will be examined more extensively to answer questions regarding the interrelatedness of viral genes that induce weakness and inflammation. This study will identify which determinants of the virus interact with the host to precipitate the development of chronic immunopathic disease. Focused, mechanistic hypotheses can then be developed to explore these interactions in future studies.

既往肠道病毒感染与某些人类自身免疫性疾病的发病机制有关，包括特发性炎症性肌病、青少年发病的糖尿病和心肌病，以及慢性疲劳综合征等非炎症性疾病。 肠道病毒感染的要素如何与病毒后疾病的发展相关尚不清楚，但该过程可能是由病毒和宿主基因组固有的因素驱动的，也可能是由这些因素与其他环境刺激的相互作用驱动的。 该提案的重点是确定对慢性炎症性肌病（CIM）小鼠模型中疾病诱导至关重要的特定病毒基因。 CIM 是通过新生儿感染柯萨奇病毒 B1 (CVB1) 在易感小鼠品系中诱导的。 已经产生了一组 CVB1 变体，这些变体在 CIM 诱导方面是肌病性 (MP) 或无肌病性 (AMP)，将用于鉴定介导 CIM 发展的病毒成分。 首先，将产生来自原型 MP 和 AMP 变体的感染性 cDNA 克隆。 克隆病毒的致病表型将在体内进行测试，以确认它们与亲本病毒相同。 然后将对两个原型病毒克隆进行测序，以识别特定的基因组差异并构建推定的肌病原性诱导区域图谱。 接下来，将通过从克隆中创建 MP/AMP 嵌合体并使用一组五个病理指标评估 CIM 诱导来测试这些差异的功能意义。 相互嵌合体的体内感染将确认哪些基因组区域与 CIM 发育相关。 然后将在单核苷酸水平上验证特定遗传差异的影响。将检查其余变体中的肌病区域，以确定 AMP 原型中的肌病变化是否保守，或者是否发生了具有相同功能效果的不同突变。 这还将揭示显性疾病决定因素是否已被绘制或是否涉及其他病毒基因。 MP3 是一种在没有炎症的情况下诱发虚弱的独特变体，将进行更广泛的检查，以回答有关诱发虚弱和炎症的病毒基因相互关系的问题。 这项研究将确定病毒的哪些决定因素与宿主相互作用，从而促进慢性免疫性疾病的发展。 然后可以提出有针对性的机制假设，以在未来的研究中探索这些相互作用。