Metabolic regulation during the two-host lifecycle of Borrelia

项目摘要/摘要 莱姆病(LD)由伯氏疏螺旋体感染引起，通过 被扁虱咬了一口。这是美国最常见的节肢动物传播疾病。胡麻B. 伯氏杆菌维持在自然的地方病循环中，在脊椎动物宿主之间交替 水库，通常是一种小型哺乳动物，还有一只硬蜱。伯氏杆菌如何感知和适应 这些完全不同的环境，以完成其地方病循环，从而坚持保持公众 健康问题，还没有得到很好的理解。在这个应用程序中，我们建议调查一部小说 调节伯氏杆菌与其壁虱载体相互作用的信号通路。我们的中央 假设是由被忽视的代谢物甲基乙二醛(MG)介导的羰基应激， 在扁虱体内螺旋体的持续存在中起着重要作用。镁是由细菌产生的 甲基乙二醛合成酶(MGSA)，用于将二羟丙酮磷酸转化为MG和 无机磷酸盐。我们的初步数据表明，这种活动很可能发生在扁虱身上， 依赖于mGsA，并在翻译后糖化特定的靶蛋白。在目标1中，我们 建议从遗传学和生物化学的角度定义羰基应激途径及其调控 伯格多尔菲氏杆菌的MG生产。我们还将研究羰基应激途径的作用。 在扁虱-小鼠LD模型中，并鉴定MG糖基化的靶蛋白。在我们的 第二个目的，我们提出通过比较的方法从遗传学角度剖析疏螺旋体的mgsA功能 用RF疏螺旋体和B.mayonii进行分析，以更好地了解羰基应激在 活着。我们建议的长期目标是了解独特的战略和 伯氏杆菌在扁虱体内持续存在并传播给哺乳动物的机制，这可能会导致 改进诊断、预防和治疗战略；这与 该机构为了减轻人类疾病而“寻求基础知识”。

PROJECT SUMMARY/ABSTRACT Lyme disease (LD) results from infection with the spirochete Borrelia burgdorferi transmitted via the bite of a tick. It is the most common arthropod-borne disease in the United States. B. burgdorferi is maintained in a natural enzootic cycle, alternating between a vertebrate host reservoir, usually a small mammal, and an Ixodes tick. How B. burgdorferi senses and adapts to these disparate environments to complete its enzootic cycle, and thus persist to remain a public health problem, is not well understood. In this application, we propose to investigate a novel signaling pathway that regulates the interaction of B. burgdorferi with its tick vector. Our central hypothesis is that carbonyl stress, mediated by the overlooked metabolite methylglyoxal (MG), has an important role in persistence of the spirochete in the tick. MG is produced in bacteria by methylglyoxal synthase (MgsA), which converts dihydroxyacetone phosphate to MG and inorganic phosphate. Our preliminary data indicate that this activity is likely to occur in the tick, is dependent on MgsA and post-translationally glycates specific target proteins. In Aim 1, we propose to genetically and biochemically define the carbonyl stress pathway and the regulation of MG production in B. burgdorferi. We will also examine the role of the carbonyl stress pathway in the tick-mouse model of LD and identify the proteins targeted for glycation by MG. In our second aim, we propose to genetically dissect MgsA function in LD Borrelia by comparative analyses with RF Borrelia and B. mayonii to better understand the role of carbonyl stress in vivo. The long-term objective of our proposal is to understand the unique strategies and mechanisms B. burgdorferi uses to persist in the tick and transmit to mammals, which may lead to improved diagnostic, prevention, and treatment strategies; this is relevant to the mission of the agency to “seek fundamental knowledge” for the sake of alleviating human disease.