Pathogenesis of Arthritis and Myositis-Associated Alphaviruses

描述(申请人提供)：蚊子传播的甲型病毒，如基孔肯雅病毒(CHIKV)和罗斯河病毒(RRV)，会在世界各地的人们中引起关节和骨骼肌组织的衰弱炎症。利用RRV诱导的小鼠疾病模型，研究表明巨噬细胞和补体系统在启动RRV诱导的炎症和促进疾病的组织破坏性阶段中发挥关键作用。巨噬细胞具有广泛的促炎、组织破坏和组织重塑/修复功能，然而，体内感染后宿主和病毒调节这些效应功能的机制尚不清楚。我们的初步研究表明，补体系统部分通过CR3调节RRV诱导的炎性巨噬细胞和疾病的激活表型，CR3是一种与补体激活产物iC3b结合的信号受体，提示RRV诱导的补体激活在炎性巨噬细胞内触发了与严重疾病和组织病理相关的基因表达程序。在其他工作中，我们已经鉴定出一种独特的RRV毒株，它在体外和体内复制类似于强毒株，但未能在关节和肌肉组织中诱导炎症，这表明特定的病毒遗传元件有助于诱导严重的宿主炎症反应，而不依赖于对体内复制的影响。这项应用的具体目的将使用体内、遗传学和分子方法来i)研究CR3在甲病毒诱导的炎症性疾病的不同阶段调节RRV诱导的炎性单核/巨噬细胞的激活表型中的作用，ii)研究补体激活片段的额外受体C3aR和/或C5aR是否促进RRV诱导的疾病，以及iii)确定RRV诱导的补体激活和/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/肌炎相关的甲型病毒是一种新的威胁，因为它们能够引发爆炸性流行病并在新的地区引起疾病。这里提出的研究将有助于理解病毒和免疫系统如何导致对感染者有害的严重炎症。由于炎症是许多人类疾病的中心特征，无论是病毒性疾病还是非病毒性疾病，这项工作可能会提供对炎症有益或有害的调控的总体洞察。

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.