Understanding Unique Aspects of Motility and Chemotaxis in Borrelia burgdorferi

 描述(申请人提供)：莱姆病是美国最流行的壁虱传播疾病。伯氏疏螺旋体是伯氏疏螺旋体的病原体，在其感染周期中具有高度的运动性，可以穿越哺乳动物和节肢动物体内的复杂环境。这一应用的中心假设是，BB的运动性和趋化性构成了一个独特的范式，并在宿主-媒介循环以及疾病过程中发挥关键作用，如传播、组织趋向性和免疫逃避。在我们的上一个资助期间，关于BB运动和趋化性的几个独特方面被揭开了面纱。在与其他几个小组的合作下，我们将BB运动性研究推向了前沿，现在BB已经成为深入了解螺旋体运动性和趋化性的范例。在这一更新应用中，将进行一项全面的研究，以阐明解释我们观察到的独特方面的分子机制以及它们与BB致病性的联系。BB有7-11个定位于细胞极点的周质鞭毛(PFS)。它们形成一条独特的丝带包裹在细胞圆柱体上，细胞圆柱体既具有骨骼功能，又具有运动功能。这种独特的排列和功能在任何其他鞭毛细菌中都没有报道。目标1将定义控制PFS数量和位置的分子机制，并确定这种控制机制如何影响BB的毒力。作为一种地方病病原体，BB有两条不同的化学感受途径。已有假说认为，在感染周期中，这两条途径在不同的宿主中发挥作用，例如，一条在哺乳动物身上，另一条在扁虱身上。目标2将破译趋化性的独特方面及其在BB地方性循环中的作用。BB是高度能动性的，在小鼠真皮中运行(快10倍)宿主免疫细胞。我们推测，这种能力允许BB在细胞免疫反应之前通过致密的皮肤组织迅速传播，然后传播到哺乳动物的远端器官。目标3将通过使用最新开发的实时成像技术分析小鼠的两个运动性和趋化性突变来验证我们的假设。这次更新中提出的所有研究都是新的，还没有在任何螺旋体中进行过。这些研究的完成将使对BB运动性和趋化性的分子分析达到一个新的水平，并了解它们在莱姆病发病机制中的确切作用。此外，这里要获得的基本知识是高影响力的，可以帮助理解其他致病螺旋体的独特运动性。

 DESCRIPTION (provided by applicant): Lyme disease is the most prevalent tick-borne disease in the United States. Borrelia burgdorferi (Bb), the causative agent, is highly motile and can traverse complex environments inside mammalian and arthropod hosts during its infectious cycle. The central hypothesis of this application is that the motility and chemotaxis of Bb constitute a unique paradigm and play a pivotal role in the host-vector cycle as well as in the disease process, e.g., dissemination, tissue tropism, and immune evasion. During our last funding period, several unique aspects about Bb motility and chemotaxis were unveiled. In collaboration with several other groups, we have pushed Bb motility research to the forefront, and now Bb has emerged as a paradigm for in-depth understanding of spirochete motility and chemotaxis. In this renewal application, a comprehensive study will be carried out to elucidate the molecular mechanisms that account for the unique aspects that we have observed as well as their links to Bb pathogenicity. Bb has 7-11 internally localized periplasmic flagella (PFs) nea the cell poles. They form a distinct ribbon wrapping around the cell cylinder, which have both skeletal and motility functions. This unique arrangement and function have not been reported in any other flagellated bacteria. Aim 1 will define the molecular mechanism that controls the number and placement of PFs and determine how this control mechanism affects the virulence of Bb. As an enzootic pathogen, Bb has two different chemosensory pathways. It has been hypothesized that these two pathways function in different hosts during the infectious cycle, e.g., one in mammals and the other in ticks. Aim 2 will decipher the unique aspect of chemotaxis and its role in the enzootic cycle of Bb. Bb is highly motile and outruns (>10-fold faster) host immune cells in mouse dermis. We hypothesize that this ability allows Bb to rapidly disseminate through dense skin tissue ahead of the cellular immune responses and then to disseminate to distal organs in mammals. Aim 3 will test our hypothesis by analyzing two motility and chemotaxis mutants in mice using recently developed live-imaging techniques. All of the studies proposed in this renewal are novel and have not been carried out in any spirochetes. Completion of these studies will lead to a new level of molecular analysis of Bb motility and chemotaxis as well as an understanding of their precise roles in the pathogenesis of Lyme disease. In addition, the fundamental knowledge to be gained here is high-impact and could aid in the understanding of the unique motility in other pathogenic spirochetes.