Role of the Shk-Grr pathway in infection of the Lyme disease spriochete

描述(申请人提供)：莱姆病是美国和欧洲最常见的节肢动物传播的传染病。这种病原体，伯氏杆菌，通过扁虱叮咬将人类作为意外宿主感染。人们对疏螺旋体成分对感染或毒力的重要性知之甚少。我们的长期目标是阐明毒力决定因素和毒力机制，作为开发治疗莱姆关节炎和预防该病的治疗方案的先决条件。本应用的目的是确定Shk-GrR信号系统在伯氏杆菌感染循环中的作用。通过在伯氏杆菌感染性菌株中产生Shk-GrR缺陷突变体，我们的初步研究导致假设Shk-GrR参与了壁虱载体中螺旋体的适应。为了验证这一假设，我们建议1)定量测定突变株在进食过程中不同时间点的小鼠不同器官以及扁虱中的螺旋体载量。这样的研究应该准确地指出突变体在其自然周期中的确切缺陷(S)；2)通过微阵列方法全面检查Shk-GrR缺陷对基因表达的影响。这些目标的实现不仅将对我们理解伯氏杆菌的感染循环产生重要影响，而且将从总体上提高我们对病媒-病原体相互作用和细菌信号转导的理解。 完成这项提案中概述的具体目标可能会发现一种新的调控途径，这对莱姆病病原体的感染循环非常重要。这不仅将促进我们对莱姆病发病机制的分子机制的理解，而且将有助于发现新的抗微生物靶点来扰乱病原体的传播周期。

DESCRIPTION (provided by applicant): Lyme disease is the most commonly reported arthropod-borne infectious disease in the United States and Europe. The causative agent, B. burgdorferi, infects humans as accidental hosts via tick bites. Little is known about the importance of Borrelia components to infection or virulence. Our long-term goal is to elucidate virulence determinants and mechanisms of virulence as a prerequisite to developing therapeutic protocols for treatment of Lyme arthritis and prevention of the disease. The objective of this application is to determine the role of the Shk-Grr putative signaling system in the infectious cycle of B. burgdorferi. By generating the Shk-Grr-deficient mutants in infectious B. burgdorferi strains, our preliminary studies lead to the hypothesis that Shk-Grr is involved in spirochete adaptation in tick vectors. To test this hypothesis, we propose 1), to quantitatively determine the mutants' spirochete loads in various mouse organs as well as in ticks at various time points during feeding. Such studies should pinpoint the exact defect(s) of the mutant during its natural cycle; 2) to globally examine the influence of Shk-Grr-deficiency in gene expression by a microarray approach. Accomplishing the proposed aims will not only have an important impact in our understanding of the infectious cycle of B. burgdorferi, but also improve our understanding of vector- pathogen interaction and bacterial signal transduction in general. Accomplishing the specific aims outlined in this proposal will likely yield the discovery of a new regulatory pathway that is important for the infectious cycle of the Lyme disease pathogen. This will not only advance our understanding the molecular mechanism of the pathogenesis of Lyme disease, but also will lead to identification of new antimicrobial targets for disrupting the pathogen's transmission cycle.