Role of Borrelia Integrin binding proteins in Lyme arthritis

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，莱姆病的病原体伯氏疏螺旋体从一种名为基质金属蛋白酶的酶家族中诱导宿主蛋白酶，这些酶作为宿主免疫反应的一部分被激活，是由机体引起的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杆菌和激活宿主免疫反应的信号通路和受体。有趣的是，Toll样受体2(TLR2)是研究最广泛的鱼腥草产物受体，对于关节炎的发生和细胞因子和趋化因子的释放并不是严格要求的。我们鉴定了一种以前未知的伯氏杆菌产物的受体，整合素31，并表明它在诱导炎症介质方面发挥着主要作用。 在这个建议中，我们研究了这两个先天免疫信号通路，整合素3，1和TLR，并确定它们在莱姆关节炎的发展和感染控制中的作用。在其他生物中的动物研究表明，整合素信号可能在炎症中起主要作用，对感染控制只有很小的影响，而TLR信号相反，在感染控制中起主要作用，在炎症中起次要作用。在第一个特定目标中，我们将测试我们已经确定的伯氏杆菌整合素31结合配体的作用。我们将构建已识别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，我们将系统地研究通过整合素31和TLR识别伯氏杆菌激活的信号通路。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3、1和TLR信号之间存在相互作用。利用从检查每个受体激活的通路中的交叉点获得的信息和激活的时间，我们将检验关于这两条通路如何相交的具体假设。 由于莱姆关节炎(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治疗方法发展的目标，可以在不延迟感染恢复的情况下减少疾病的发病机制。

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.