Pathogenesis of Arthritis and Myositis-Associated Alphaviruses

关节炎和肌炎相关甲病毒的发病机制

• 批准号: 7808916
• 负责人: Thomas E Morrison
• 金额: $ 10.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-25 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808916
• 关键词: Alphavirus; Area; Arthritis; C3bi; Cells; Characteristics; Chikungunya virus; Complement Activation; Complementary DNA; Country; Culicidae; Development; Disease; Epidemic; Gene Expression; Genetic; Genome; Glycoproteins; ITGAM gene; Immune response; Immune system; In Vitro; Indian Ocean; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Joints; Laboratories; Lectin; Macrophage-1 Antigen; Mayaro virus; Molecular Genetics; Molecular Profiling; Mus; Muscle; Mutation; Myositis; Pathogenesis; Pathology; Pathway interactions; Persons; Phase; Phenotype; Play; Regulation; Research Personnel; Rivers; Role; Ross river virus; Severities; Signal Transduction; Site; Skeletal Muscle; Testing; Tissues; Viral; Virulent; Virus; Virus Activation; Virus Diseases; Work; activation product; complement system; design; effective therapy; genetic element; glycosylation; human disease; in vivo; insight; macrophage; monocyte; mouse model; new therapeutic target; programs; receptor; receptor binding; research study; virus genetics; virus pathogenesis

DESCRIPTION (provided by applicant): Mosquito-transmitted alphaviruses, such as chikungunya virus (CHIKV) and Ross River virus (RRV), cause debilitating inflammation of joint and skeletal muscle tissue in people worldwide. Utilizing a mouse model of RRV-induced disease, studies have demonstrated critical roles for macrophages and the complement system in initiation of RRV-induced inflammation and promotion of the tissue destructive phase of the disease. Macrophages have broad proinflammatory, tissue destructive, and tissue remodeling/reparative capabilities, however, the host and viral mechanisms that regulate these effector functions following infection in vivo is not well understood. Our preliminary studies indicate that the complement system regulates the activation phenotype of RRV-induced inflammatory macrophages and disease partly through CR3, a signaling receptor that binds the complement activation product iC3b, suggesting that RRV-induced complement activation triggers a gene expression program within inflammatory macrophages that is associated with severe disease and tissue pathology. In other work, we have identified a unique RRV strain that replicates similar to the virulent strain in vitro and in vivo, yet fails to induce inflammation in joint and muscle tissue, suggesting that specific viral genetic elements contribute to the elicitation of a severe host inflammatory response independent of effects on in vivo replication. The specific aims of this application will use in vivo, genetic, and molecular approaches to i) investigate the role of CR3 in regulation of the activation phenotype of RRV-induced inflammatory monocytes/macrophages during distinct phases of alphavirus-induced inflammatory disease, ii) investigate whether C3aR and/or C5aR, additional receptors for complement activation fragments, promote RRV-induced disease, and iii) identify viral genetic elements required for RRV-induced complement activation and/or immunopathologic macrophage inflammation. Relevance: Arthritis/myositis-associated alphaviruses are an emerging threat due to their ability to initiate explosive epidemics and to cause disease in new areas. The studies proposed here will help understand how both the virus and the immune system contribute to severe inflammation that is detrimental to the infected person. Because inflammation is a central characteristic of many human diseases, both viral and nonviral, this work may provide general insight into how beneficial or harmful inflammation is regulated.

描述（由申请人提供）：蚊子传播的α病毒，例如Chikungunya病毒（Chikv）和Ross River病毒（RRV），导致全球人的关节和骨骼肌组织的炎症使人衰弱。利用RRV诱导疾病的小鼠模型，研究表明，巨噬细胞和补体系统在启动RRV诱导的炎症和促进该疾病的组织破坏阶段的关键作用。巨噬细胞具有广泛的促炎，组织破坏性和组织重塑/修复能力，但是，在体内感染后调节这些效应子功能的宿主和病毒机制尚不清楚。我们的初步研究表明，补体系统调节RRV诱导的炎症性巨噬细胞的激活表型和疾病部分通过CR3，这是一种结合补体激活产物IC3B的信号受体，这表明RRV诱导的补体激活诱导了与炎症性巨噬细胞中的基因表达程序，这与严重疾病的炎症性疾病相关。在其他工作中，我们已经确定了一种独特的RRV菌株，该菌株复制了类似于体外和体内的毒素菌株，但未能诱导关节和肌肉组织中的炎症，这表明特定的病毒遗传元素有助于引起严重的宿主炎症反应对体内重复的影响无关。 The specific aims of this application will use in vivo, genetic, and molecular approaches to i) investigate the role of CR3 in regulation of the activation phenotype of RRV-induced inflammatory monocytes/macrophages during distinct phases of alphavirus-induced inflammatory disease, ii) investigate whether C3aR and/or C5aR, additional receptors for complement activation fragments, promote RRV-induced disease, and iii)确定RRV诱导补体激活和/或免疫病理巨噬细胞炎症所需的病毒遗传元件。相关性：关节炎/与肌炎相关的α病毒是一种新的威胁，因为它们能够启动爆炸性流行病并在新地区引起疾病。这里提出的研究将有助于了解病毒和免疫系统如何导致严重的炎症，这对感染者有害。由于炎症是许多人类疾病的核心特征，包括病毒和非病毒病毒，这项工作可能会提供有关如何调节有益或有害炎症的一般见解。