Togavirus Tropism for Bones, Joints, and CNS

描述（由申请人提供）：病毒诱导的炎性疾病，包括关节炎、肺炎和脑炎，是人类疾病的重要原因，并且显然需要提高我们对这种不同病症的发病机制的整体理解。披膜病毒，包括蚊媒甲病毒，如基孔肯雅病毒、奥龙病毒和罗斯河病毒，引起感染性关节炎/关节痛/肌痛的大规模爆发，影响数千至数百万人，并继续成为一种新兴的威胁。然而，尽管这些病毒可以大规模地引起严重的风湿性疾病，但对它们的发病机制知之甚少。我们和其他人已经开发了RRV诱导的关节炎和肌炎的小鼠模型，其中病毒在滑膜关节和骨骼肌中复制到高水平，但病毒诱导的疾病依赖于主要由巨噬细胞组成的免疫病理学炎症反应。对调节这种反应的宿主因子的研究表明，病毒诱导的组织破坏的发展需要宿主补体级联的激活，而不是将炎性细胞募集到病毒感染的组织中。因此，本提案的目的是研究补体在RRV诱导的疾病的发病机制中所起的作用，包括分析RRV感染激活补体系统的机制以及补体在调节免疫病理炎症反应中的下游功能。我们还建议将这些研究从小鼠模型扩展到人类疾病，以确定补体激活是否是患有甲病毒诱导的关节炎的个体中病毒诱导的炎症反应的组成部分。因此，这项工作将大大提高我们对披膜病毒诱导的关节炎/肌痛的发病机制的理解，同时也提供了新的病毒与宿主补体级联反应和炎症反应的相互作用的见解，这可能最终导致更好地理解调节其他病理性病毒诱导的炎症反应的机制，如发生在病毒性关节炎，脑炎或肺炎。

DESCRIPTION (provided by applicant): Virus-induced inflammatory diseases, including arthritis, pneumonia, and encephalitis, are a significant cause of human disease, and there is a clear need to improve our overall understanding of the pathogenesis of this diverse array of conditions. Togaviruses, which include the mosquito-borne alphaviruses such as Chikungunya, O'nyong-nyong, and Ross River virus cause massive outbreaks of infectious arthritis/athralgia/myalgia affected thousands to millions of individuals and continue to be an emerging threat. However, even though these viruses can cause severe rheumatic disease on a massive scale, relatively little is known about their pathogenesis. We and others have developed a mouse model of RRV-induced arthritis and myositis, where the virus replicates to high levels in the synovial joints and skeletal muscle, but virus induced disease is dependent on an immunopathologic inflammatory response largely comprised of macrophages. Studies on the host factors that regulate this response demonstrated that activation of the host complement cascade is required for the development of virus-induced tissue destruction, but not recruitment of inflammatory cells into the virus-infected tissues. Therefore, the objectives of this proposal are to investigate the role that complement plays in the pathogenesis of RRV- induced disease, including analysis of the mechanisms by which RRV infection activates the complement system and the downstream functions of complement in regulating the immunopathologic inflammatory response. We also propose to extend these studies from the mouse model back to the human disease in order to determine whether complement activation is a component of the virus-induced inflammatory response in individuals suffering from alphavirus-induced arthritis. Therefore, this work will significantly enhance our understanding of the pathogenesis of Togavirus-induced arthritis/myalgia, while also providing insights into novel viral interactions with the host complement cascade and inflammatory response that may ultimately lead to better understanding of the mechanisms that regulate other pathologic virus-induced inflammatory responses, such as occur in viral arthritis, encephalitis, or pneumonia.