Metabolic regulation during the two-host lifecycle of Borrelia

项目总结/摘要 莱姆病（LD）是由感染伯氏疏螺旋体螺旋体通过 蜱虫的叮咬它是美国最常见的节肢动物传播疾病。B。 burgdorferi维持在一个自然的地方性循环中，在脊椎动物宿主 水库，通常是一个小哺乳动物，和硬蜱蜱。怎么样B。burgdorferi感觉并适应 这些完全不同的环境完成其地方病循环，从而坚持保持公共 健康问题，并没有得到很好的理解。在本申请中，我们提出研究一种新的 调节B相互作用的信号通路。burgdorferi和它的蜱虫载体。我们的中央 假设是由被忽视代谢物甲基乙二醛（MG）介导的羰基应激， 在蜱虫体内螺旋体的持续存在中起着重要作用。MG由细菌产生， 甲基乙二醛合酶（MgsA），其将磷酸二羟丙酮转化为MG， 无机磷酸盐我们的初步数据表明，这种活动很可能发生在蜱虫中， 依赖于MgsA和免疫后标记的特异性靶蛋白。目标1： 建议从遗传学和生物化学上确定羰基应激途径和调控 B的MG产量。burgdorferi。我们还将研究羰基应激途径的作用 在LD的蜱鼠模型中，并鉴定MG糖基化的靶蛋白。在我们 第二个目的，我们建议通过比较，从遗传学角度剖析LD疏螺旋体中MgsA的功能， 用RF疏螺旋体和B分析。为了更好地了解羰基应激在 vivo.我们的提案的长期目标是了解独特的战略， 机制B。burgdorferi用于坚持蜱和传播给哺乳动物，这可能导致 改进诊断、预防和治疗策略;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.