Regulatory Network of the Lyme Disease Pathogen

摘要 莱姆病是一种新出现的硬蜱传播疾病，是我国重要的公共卫生问题。 美国。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)和啮齿动物之间穿越其地方性循环时的表达 哺乳动物的宿主。在过去的几年里，PI之前的工作发现了一个中央监管机构 在伯氏假单胞菌中，rpos途径。Rpos途径是伯氏杆菌的守门人。 从扁虱身上排出并感染哺乳动物。Rpos控制着许多抗原和毒力因子 哺乳动物感染。PI之前的工作，以及其他人，证明了转录 Rpos的激活受西格玛因子54(σ54)和细菌增强子结合的控制。 蛋白质(EBP)、RRP2。在其他细菌中已经很好地确立了EBP是必不可少的，并且足以 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 十年前由两个小组独立发现，并表明BosR直接调节RPO 转录自其σ54型启动子。BosR如何适应这一途径是我们的一个重大差距 对rpos途径的理解。基于我们的初步研究，我们提出了一项挑衅性的 假设：BosR不是转录激活剂；相反，BosR是一种新的RNA结合蛋白， 结合rpos mRNA，稳定其周转。我们将在目标1中测试这一假设。 已经确定了调节rpos途径的因素，我们成功地开发了一种 用于识别影响rpos调控的基因的遗传筛选。这样的屏幕使我们能够 识别调节rpos途径的全基因组新因子，揭示全面的 Rpos通路是如何调控的，以及多种信号如何影响该通路。 目的2中提出了Bb在扁虱载体和哺乳动物宿主之间的地方性循环。

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.