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

 描述（由申请人提供）：莱姆病是美国报告最多的病媒传播疾病。病原体伯氏疏螺旋体（Bb）是一种专性致病螺旋体，通过蜱叮咬传播。Bb是如何维持在哺乳动物和蜱之间的地方性流行周期中的，人们对此知之甚少;然而，这种理解对于开发创新方法来破坏蜱-哺乳动物-蜱的自然周期至关重要。我们和其他人已经确定了一个双组分信号转导系统，Hk 1-Rrp 1，这是必不可少的Bb生存在蜱。Rrp 1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GMP（c-di-GMP），这是一种新的细菌第二信使，可控制能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介导的信号传导控制从哺乳动物到蜱的转变后，从葡萄糖到甘油的分解代谢开关，通过调节glp操纵子的转录甘油的运输和利用，这是至关重要的螺旋体生存在蜱。此外，我们发现，c-di-GMP结合效应蛋白PlzA，以前已知的影响Bb运动，也控制glp的表达以及合成的多种毒力因子。我们假设，由于小的基因组和精简的调控库，Bb采用相同的c-di-GMP效应蛋白，PlzA，或与PlzA相互作用的蛋白质，以协调不同的过程（运动，catalysts，毒力），参与了哺乳动物到蜱的过渡。为了验证这一假设并了解 本研究的主要目的是：（1）阐明Bb中c-di-GMP结合蛋白PlzA对甘油代谢和毒力的调节机制;（2）鉴定和表征Bb中新的c-di-GMP结合效应蛋白，并探讨其在蜱存活中的作用。成果 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信号传导模式。

 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.