Role of Borrelia Integrin binding proteins in Lyme arthritis

疏螺旋体整合素结合蛋白在莱姆关节炎中的作用

• 批准号: 8077625
• 负责人: Linden T Hu
• 金额: $ 35.78万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077625
• 关键词: Acute suppurative arthritis due to bacteria; Adaptor Signaling Protein; Animal Model; Animals; Area; Arthritis; Attenuated; Bacteria; Bacterial Infections; Binding; Binding Proteins; Borrelia; Borrelia burgdorferi; C Type Lectin Receptors; Cartilage; Chronic; Collagen; Complement; Complex; Data; Development; Disease; Dominant-Negative Mutation; Enzymes; Exhibits; Family; Future; Gelatin; Immune; Immune response; Immune system; In Vitro; Incidence; Infection; Infection Control; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Integrin Binding; Integrin Signaling Pathway; Integrins; Joints; Knockout Mice; Laminin; Left; Ligand Binding; Ligands; Lipoproteins; Lyme Arthritis; Lyme Disease; Matrix Metalloproteinases; Mediating; Minor; Myelogenous; Natural Immunity; Organ; Organism; Pathogenesis; Pathology; Pathway interactions; Pattern recognition receptor; Peptide Hydrolases; Play; Public Health; Receptor Signaling; Recovery; Reporting; Rheumatoid Arthritis; Role; Shapes; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; Symptoms; Testing; Time; Toll-Like Receptor 1; Toll-Like Receptor 2; Toll-like receptors; United States; Up-Regulation; Vector-transmitted infectious disease; Viral; Work; cell type; chemokine; cytokine; enzyme pathway; inhibitor/antagonist; insight; knockout animal; microbial; microbial host; microorganism; mouse model; mutant; protein B; receptor; therapy development; tool

Lyme disease is the most common vector-borne disease in the U.S. and and an important public health problem whose incidence continues to increase. In our preliminary work, we have shown that Borrelia burgdorferi, the causative agent of Lyme disease, induces host proteases from a family of enzymes called matrix metalloproteinases and that these enzymes, which are activated as part of the host immune response, are responsible for much of the cartilage degradation and arthritis caused by the organism. We have identified signaling pathways and receptors involved in the recognition of B. burgdorferi and activation of the host immune response. Interestingly, the most widely studied receptor for borrelial products, toll-like receptor 2 (TLR2) is not strictly required for the development of arthritis and release of cytokines and chemokines. We identified a previously unrecognized receptor of B. burgdorferi products, integrin 31, and showed that it plays a major role in induction of inflammatory mediators. In this proposal, we examine these two innate immune signaling pathways, integrin 31 and TLRs, and determine their contributions to the development of Lyme arthritis and control of infection. Animal studies in other organisms have suggested that integrin signaling may play a major role in inflammation with only a minor impact on control of infection whereas TLR signaling is the opposite, with a major role in control of infection and a lesser role in inflammation. In the first specific aim, we will test the role of a putative integrin 31 binding ligand of B. burgdorferi that we have identified. We will construct deletion mutants of the identified binding protein and test the ability of the mutant and a complemented mutant to infect, disseminate and cause arthritis in a mouse model. In the second aim, we will systematically examine signaling pathways activated by recognition of B. burgdorferi through integrin 31 and TLRs. Recent studies suggest that the innate immune response is shaped by “cross-talk” between different families of receptors. Our preliminary data suggests that there is an interaction between signaling from integrin 31 and TLRs. Using information garnered from examining the intersections in the pathways that are activated by each receptor and the timing of activation, we will test specific hypotheses as to how these two pathways may intersect. Because pathology in Lyme arthritis (and many other forms of arthritis) is predominantly due to activation of the host immune system, by better understanding the pathways that direct inflammation and that control infection, we hope to identify areas of divergence that will be targets for future development of therapies that can reduce the pathogenesis of disease without delaying recovery from infection.

莱姆病是美国最常见的媒介传播疾病，也是一个重要的公共卫生问题，其发病率持续上升。在我们的初步工作中，我们已经证明了伯氏疏螺旋体，莱姆病的病原体，诱导宿主蛋白酶家族中的基质金属蛋白酶，这些酶作为宿主免疫反应的一部分被激活，是导致软骨退化和关节炎的主要原因。我们已经确定了参与识别伯氏疏螺旋体和激活宿主免疫反应的信号通路和受体。有趣的是，最广泛研究的borrelial产品受体toll样受体2 （TLR2）在关节炎的发展和细胞因子和趋化因子的释放中并不是严格必需的。我们发现了一种以前未被识别的伯氏疏螺旋体产物受体，整合素31，并表明它在炎症介质的诱导中起主要作用。