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

描述（由申请人提供）：莱姆病是美国和欧洲最常见的节肢动物传播的传染病。病原体，B。burgdorferi通过蜱叮咬作为偶然宿主感染人类。关于疏螺旋体组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，作为制定治疗方案的先决条件，用于治疗莱姆关节炎和预防疾病。本申请的目的是确定Shk-Grr推定信号系统在B感染周期中的作用。burgdorferi。通过在感染性B.对于伯氏螺旋体菌株，我们的初步研究导致Shk-Grr参与蜱媒介中螺旋体适应的假设。为了验证这一假设，我们建议1），定量测定突变体的螺旋体负荷在不同的小鼠器官以及蜱在不同的时间点在喂养。这些研究应该精确定位突变体在其自然周期中的确切缺陷; 2）通过微阵列方法全面检查Shk-Grr缺陷对基因表达的影响。实现所提出的目标不仅将对我们理解B的传染周期产生重要影响。burgdorferi，而且还提高了我们对载体-病原体相互作用和细菌信号转导的一般理解。 实现本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周期很重要。这不仅将促进我们对莱姆病发病机制的理解，而且还将导致确定新的抗菌靶标，以破坏病原体的传播周期。

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.