Role of Borrelia Integrin binding proteins in Lyme arthritis

莱姆病是美国最常见的病媒传播疾病，也是一个重要的公共卫生问题，其发病率持续增加。在我们的初步工作中，我们已经表明莱姆病的病原体伯氏疏螺旋体诱导来自称为基质金属蛋白酶的酶家族的宿主蛋白酶，并且这些酶作为宿主免疫应答的一部分被激活，是由生物体引起的软骨降解和关节炎的主要原因。我们已经确定了参与B识别的信号通路和受体。burgdorferi和宿主免疫应答的激活。有趣的是，疏螺旋体产物的最广泛研究的受体，toll样受体2（TLR2）对于关节炎的发展和细胞因子和趋化因子的释放不是严格需要的。我们鉴定了一种以前未被认识的B受体。Burgdorferi产物，整合素β 3 β 1，并显示其在诱导炎症介质中起主要作用。 在这个提议中，我们研究了这两个先天免疫信号通路，整合素β 3 β 1和TLR，并确定它们对莱姆病关节炎发展和感染控制的贡献。在其他生物体中的动物研究表明，整合素信号传导可能在炎症中起主要作用，对感染控制的影响很小，而TLR信号传导则相反，在感染控制中起主要作用，在炎症中起较小作用。在第一个具体目标中，我们将测试推定的整合素β 3 β 1结合B配体的作用。我们已经确认的伯氏螺旋体我们将构建所鉴定的结合蛋白的缺失突变体，并在小鼠模型中测试突变体和互补突变体感染、传播和引起关节炎的能力。在第二个目标中，我们将系统地研究识别B激活的信号通路。通过整合素β 3 β 1和TLRs介导的伯氏螺旋体感染。最近的研究表明，先天免疫反应是由不同受体家族之间的“串扰”形成的。我们的初步数据表明，整合素β 3 β 1和TLR的信号传导之间存在相互作用。利用从检查由每个受体激活的通路中的交叉点和激活的时间获得的信息，我们将测试关于这两个通路如何交叉的特定假设。 由于莱姆病关节炎（和许多其他形式的关节炎）的病理主要是由于宿主免疫系统的激活，通过更好地了解直接炎症和控制感染的途径，我们希望确定分歧的领域，这些领域将成为未来开发治疗的目标，可以减少疾病的发病机制，而不会延迟感染的恢复。

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.