Pathogenesis of Arthritis and Myositis-Associated Alphaviruses

描述（由申请方提供）：蚊传播的甲病毒，如基孔肯雅病毒（CHIKV）和罗斯河病毒（RRV），在全世界范围内引起关节和骨骼肌组织的衰弱性炎症。利用RRV诱导的疾病的小鼠模型，研究已经证明巨噬细胞和补体系统在RRV诱导的炎症的起始和疾病的组织破坏阶段的促进中的关键作用。巨噬细胞具有广泛的促炎、组织破坏和组织重塑/修复能力，然而，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诱导的炎性巨噬细胞和疾病的活化表型，部分通过CR 3，一种信号受体，结合补体活化产物iC 3b，表明RRV诱导的补体活化触发炎性巨噬细胞内的基因表达程序，与严重的疾病和组织病理学。在其他工作中，我们已经确定了一个独特的RRV株，复制类似的强毒株在体外和体内，但未能诱导关节和肌肉组织的炎症，这表明特定的病毒遗传元件有助于引发严重的宿主炎症反应独立于体内复制的影响。本申请的具体目的将使用体内、遗传和分子方法来i）研究CR 3在甲病毒诱导的炎性疾病的不同阶段期间在调节RRV诱导的炎性单核细胞/巨噬细胞的活化表型中的作用，ii）研究补体活化片段的另外的受体C3 aR和/或C5 aR是否促进RRV诱导的疾病，和iii）鉴定RRV诱导的补体激活和/或免疫病理性巨噬细胞炎症所需的病毒遗传元件。相关性：关节炎/肌炎相关甲病毒是一种新兴的威胁，因为它们能够引发爆发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了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核心特征，无论是病毒性的还是非病毒性的，这项工作可能会提供对有益或有害的炎症是如何调节的一般见解。

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.