Togavirus Tropism for Bones, Joints, and CNS

披膜病毒对骨骼、关节和中枢神经系统的趋向性

• 批准号: 7928648
• 负责人: Mark T Heise
• 金额: $ 21.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928648
• 关键词: Affect; Alphavirus; Animals; Arthralgia; Arthritis; Back; Cells; Complement; Complement Activation; Complement Membrane Attack Complex; Congo; Country; Culicidae; Disease; Disease Outbreaks; Effector Cell; Encephalitis; Epidemic; Exhibits; Fiji; Genes; Health; Human; ITGAM gene; Indian Ocean; Individual; Indonesia; Infectious Arthritis; Inflammatory; Inflammatory Response; Integration Host Factors; Joints; Knowledge; Lead; Light; Macrophage-1 Antigen; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Myalgia; Myositis; NK Cell Activation; Natural Killer Cells; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Persons; Phase; Phenotype; Play; Pneumonia; Polyarthritides; Process; Research; Research Personnel; Rheumatism; Rivers; Role; Ross river virus; Skeletal Muscle; System; Tissues; Togaviridae; Tropism; Viral; Viral Arthritis; Virus; Virus Diseases; Work; activation product; bone; cell killing; cell type; chikungunya; cytotoxic; human disease; improved; in vivo; insight; macrophage; mouse model; novel; programs; response; virus development; virus pathogenesis

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.

描述（由申请人提供）：病毒诱发的炎症性疾病，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多种疾病阵列的发病机理的整体理解。 tovaviruses，包括蚊子α，例如奇科尼亚，奥诺宁和罗斯河病毒，导致传染性关节炎/阿斯拉尔痛/肌痛爆发大量爆发，对数百万人影响了数千个人，并继续受到新兴威胁。但是，即使这些病毒可能会大规模引起严重的风湿病，但对它们的发病机理的了解很少。我们和其他人开发了一种RRV诱导的关节炎和肌炎的小鼠模型，在该模型中，该病毒在滑膜关节和骨骼肌中复制到高水平，但是病毒诱发的疾病取决于免疫病理炎症反应，主要由巨噬细胞组成。对调节这种反应的宿主因子的研究表明，宿主补体级联反应的激活是为了发展病毒诱导的组织破坏，而不是将炎性细胞募集到病毒感染的组织中。因此，该提案的目标是研究补体在RRV诱导的疾病发病机理中的作用，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病毒诱导的患有α病毒引起的关节炎的个体的炎症反应的组成部分。因此，这项工作将显着增强我们对伸缩膜诱导的关节炎/肌痛的发病机理的理解，同时还为与宿主补体级联反应的新型病毒相互作用和炎症反应提供了见解，这些病毒相互作用最终可能会更好地理解对其他病毒诱导的炎症反应的机制，例如其他病毒性反应，例如在病毒性炎中，例如发生病毒性炎，例如发生。