Cyclic di-GMP-dependent regulation of metabolism and virulence in Borrelia burgdorferi

伯氏疏螺旋体代谢和毒力的循环双 GMP 依赖性调节

• 批准号: 8871267
• 负责人: Mark Gomelsky
• 金额: $ 24.08万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871267
• 关键词: Address; Antibiotics; Arthropods; Bacteria; Bacteria sigma factor KatF protein; Binding; Binding Proteins; Biological Assay; Bite; Blood capillaries; Borrelia burgdorferi; Borrelia oxidative stress regulator; Carbon; Catabolism; Cell Cycle Regulation; Cell physiology; Development; Disease; Foundations; Gene Expression; Genes; Genetic Transcription; Genome; Glucose; Glycerol; Goals; Gram-Positive Bacteria; Individual; Infection; Laboratory mice; Life Style; Ligands; Lyme Disease; Mammals; Mediating; Metabolism; Methods; Microbial Biofilms; Midgut; Modeling; Natural Immunity; Operon; Order Spirochaetales; Outcome; Pathogenesis; Peptide Hydrolases; Play; Process; Production; Proteins; Proteomics; Radial; Regulation; Reporting; Repression; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Source; System; Testing; Ticks; Transcription Coactivator; United States; Vector-transmitted infectious disease; Virulence; Virulence Factors; Weather; Yang; bacterial vector; capillary; cell motility; diguanylate cyclase; enzootic; feeding; fitness; glucose metabolism; innovation; insight; novel; pathogen; public health relevance; response; screening; second messenger; vector

 DESCRIPTION (provided by applicant): Lyme disease is the most reported vector-borne disease in the United States. The causative agent, Borrelia burgdorferi (Bb), is an obligate pathogenic spirochete that is transmitted via a tick bite. How Bb is maintained in its enzootic cycle between mammals and ticks is poorly understood; yet, this understanding is critical for developing innovative approaches to disrupt the tick-mammal-tick natural cycle. We and others have identified a two-component signal transduction system, Hk1-Rrp1, that is essential for Bb survival in the tick. Rrp1is a response regulator possessing diguanylate cyclase (DGC) activity that produces cyclic dimeric GMP (c-di-GMP), a new bacterial second messenger that controls the switch between the motile, single-cellular lifestyle and the sessile, multicellular lifestyle (biofilms). We discovered that c-di-GMP-mediated signaling controls a catabolic switch from glucose to glycerol upon the transition from the mammal to the tick, by regulating the transcription of the glp operon for glycerol transport and utilization which are critical for spirochete survival in ticks. Further, we found that the c-di-GMP-binding effector protein PlzA, previously known to influence Bb motility, also controls glp expression as well as synthesis of multiple virulence factors. We hypothesize that, because of the small genome and streamlined regulatory repertoire, Bb employs the same c-di-GMP effector protein, PlzA, or a protein that interacts with PlzA, to coordinate diverse processes (motility, catabolism, virulence) that are involved in the mammal-to-tick transition. To test this hypothesis and to to understand the role of c-di-GMP signaling in the mammal-to-arthropod host transition, we have formulated the following Specific Aims: (1) Elucidate the mechanism of regulation of the glycerol metabolism and virulence by the c-di-GMP- binding protein PlzA in Bb; (2) Identify and characterize new c-di-GMP-binding effector proteins in Bb and interrogate their role in survival in the tick. Outcomes will uncover novel processes underlying the mammal-to-arthropod host transition, novel c-di-GMP effector proteins and new c-di-GMP signaling paradigm.

 描述（由申请人提供）：莱姆病是美国报道最多的媒介传播疾病。病原体伯氏疏螺旋体 (Bb) 是一种专性致病性螺旋体，通过蜱虫叮咬传播。人们对 Bb 在哺乳动物和蜱虫之间的地方性循环中如何维持知之甚少。然而，这种理解对于开发破坏蜱-哺乳动物-蜱自然循环的创新方法至关重要。我们和其他人已经确定了一种双组分信号转导系统 Hk1-Rrp1，它对于蜱虫中 Bb 的生存至关重要。 Rrp1 是一种具有二鸟苷酸环化酶 (DGC) 活性的反应调节剂，可产生环状二聚体 GMP (c-di-GMP)，这是一种新的细菌第二信使，控制运动的单细胞生活方式和固着的多细胞生活方式（生物膜）之间的转换。我们发现，c-di-GMP 介导的信号传导通过调节 glp 操纵子的转录来控制从哺乳动物到蜱的过渡时从葡萄糖到甘油的分解代谢转换，甘油的运输和利用对于蜱中螺旋体的生存至关重要。此外，我们发现 c-di-GMP 结合效应蛋白 PlzA（之前已知会影响 Bb 运动）也控制 glp 表达以及多种毒力因子的合成。我们假设，由于基因组较小和简化的调控系统，Bb 采用相同的 c-di-GMP 效应蛋白 PlzA 或与 PlzA 相互作用的蛋白来协调哺乳动物到蜱转变中涉及的不同过程（运动性、分解代谢、毒力）。为了检验这个假设并理解 针对哺乳动物向节肢动物宿主转变中的c-di-GMP信号传导，我们制定了以下具体目标：（1）阐明Bb中c-di-GMP结合蛋白PlzA调节甘油代谢和毒力的机制； (2) 鉴定和表征 Bb 中新的 c-di-GMP 结合效应蛋白，并探讨它们在蜱存活中的作用。结果 将揭示哺乳动物到节肢动物宿主转变的新过程、新的 c-di-GMP 效应蛋白和新的 c-di-GMP 信号传导范式。