Regulatory Network of the Lyme Disease Pathogen

摘要 莱姆病是一种新出现的蜱传疾病，也是世界上一个重要的公共卫生问题。 美国的病原体伯氏疏螺旋体（Bb）必须显著改变其基因 在节肢动物媒介（硬蜱）和啮齿动物之间的地方流行周期中表达 哺乳动物宿主在过去的几年里，PI以前的工作发现了一个中央监管机构， 途径，RpoS途径，在B中。burgdorferi。RpoS通路是B的看门人。burgdorferi 从蜱虫中排出并感染哺乳动物。RpoS控制许多抗原和毒力因子， 哺乳动物感染PI先前的工作，沿着其他人，证明了转录 rpoS的激活受sigma因子54（σ54）和细菌增强子结合蛋白的控制。 蛋白（EBP），Rrp2.在其他细菌中，EBP是必不可少的，足以 在体内和体外激活σ54型启动子。令人惊讶的是，另一家监管机构BosR被 十年前，两个研究小组独立发现了BosR，并表明BosR直接调节rpoS， 从其σ54型启动子转录。BosR如何适应这一途径是我们在这方面的一个重大差距。 了解RpoS途径。根据我们的初步研究，我们提出了一个挑衅性的 假说：BosR不是转录激活因子，相反，BosR是一种新RNA结合蛋白， 与rpoS mRNA结合并稳定其周转。我们将在目标1中检验这一假设。鉴于很少有 已经确定了调节RpoS通路的因子，我们已经成功地开发了一种 遗传筛选，用于鉴定影响RpoS调节的基因。这样的屏幕可以让我们 鉴定调节RpoS通路的全基因组新因子， RpoS通路如何调节以及多信号如何影响 目的2中提出的蜱虫载体和哺乳动物宿主之间Bb的地方流行循环。

ABSTRACT Lyme disease is an emerging tick-borne disease and an important public health problem in the United States. The causative agent, Borrelia burgdorferi (Bb), must dramatically alter its gene expression as it traverses its enzootic cycle between the arthropod vector (Ixodes ticks) and rodent mammalian hosts. In the past several years, the PI’s previous work discovered a central regulatory pathway, the RpoS pathway, in B. burgdorferi. The RpoS pathway is a gatekeeper for B. burgdorferi to exit from ticks and infect mammals. RpoS control many antigens and virulence factors for mammalian infection. The PI’s previous work, along with others, demonstrated that transcriptional activation of rpoS is under the control of the sigma factor 54 (σ54) and a bacterial enhancer-binding protein (EBP), Rrp2. It is well established in other bacteria that EBP is essential and sufficient to activate a σ54-type promoter both in vivo and in vitro. Surprisingly, another regulator, BosR, was discovered independently by two groups a decade ago and showed that BosR directly regulates rpoS transcription from its σ54-type promoter. How BosR fits into this pathway is a significant gap in our understanding of the RpoS pathway. Based on our Preliminary Studies, we propose a provocative hypothesis: BosR is not a transcriptional activator; instead, BosR is a novel RNA binding protein that binds to rpoS mRNA and stabilizes its turnover. We will test this hypothesis in Aim 1. Given that few factors have been identified for regulating the RpoS pathway, we have successfully developed a genetic screen for identifying genes that influence the regulation of RpoS. Such screen allows us to identify genome-wide novel factors that modulate the RpoS pathway, uncover a comprehensive picture of how the RpoS pathway is regulated and how multi-signals influence the pathway in the enzootic cycle of Bb between the tick vector and the mammalian host, which is proposed in Aim 2.