Host adaptation of the Lyme disease spirochete

描述（由申请方提供）：莱姆病病原体伯氏疏螺旋体（Bb）维持在涉及其节肢动物载体（硬蜱）和啮齿类哺乳动物宿主的复杂地方病循环中。Bb适应两种明显不同的宿主环境的关键策略是在蜱的取食过程中其表面蛋白的急剧变化。在过去的几年中，我们和其他人已经发现了一种新的调控途径，Rrp 2-RpoN-RpoS途径（Rrp 2途径），作为一个主要的机制，在螺旋体的地方流行周期的差异基因表达。Rrp 2通路的发现产生了两个基本问题，这对我们理解Bb的宿主适应至关重要。(i)Rrp 2途径控制的毒力因子有哪些？(ii)激活Rrp 2通路的上游信号事件是什么？我们的长期目标是通过鉴定Bb毒力因子和破译其调控机制来阐明Bb如何引起疾病。为了实现这一目标，我们制定了以下三个具体目标：i）表征由Rrp 2途径控制的候选毒力因子。ii）确定Hk 2在蜱传播和哺乳动物感染期间Rrp 2激活中的作用。我们将测试的假设，Hk 2是重要的Rrp 2在体内激活和感染周期的Bb。iii）更好地定义用于体内和体外激活Rrp 2的Hk 2依赖性和Hk 2非依赖性途径的信号传导传感机制。我们将测试的假设，Hk 2的PAS结构域是哺乳动物宿主特异性信号的受体，而乙酰-P是一个因素，有助于Hk 2独立的Rrp 2在体外和体内激活。实现特定目标1将确定对哺乳动物感染重要的新的毒力因子。目标2和3的结果将阐明Rrp 2通路的复杂信号感应机制，这将填补我们对Bb宿主适应的理解中的一个主要空白。这些发现可能会导致治疗靶点的发展，并为制定阻断Bb地方性流行周期的策略奠定基础。拟议的工作也将使我们能够深入了解其他媒介传播的细菌病原体的宿主适应。

DESCRIPTION (provided by applicant): Borrelia burgdorferi (Bb), the causative agent of Lyme disease, is maintained in a complex enzootic cycle involving its arthropod vector (Ixodes ticks) and a rodent mammalian host. The key strategy that Bb has evolved to adapt to two markedly different host environments is the dramatic alteration of its surface proteins during the process of tick feeding. In the past few years, we and others have uncovered a novel regulatory pathway, the Rrp2-RpoN-RpoS pathway (Rrp2 pathway), as a major mechanism underlying differential gene expression during the spirochete's enzootic cycle. The discovery of the Rrp2 pathway engenders two fundamental questions that are critical to our understanding of host adaptation by Bb. (i) What are the virulence factors controlled by the Rrp2 pathway? (ii) What are the upstream signaling events that activate the Rrp2 pathway? Our long-term objective is to elucidate how Bb causes disease by identifying Bb virulence factors and deciphering the mechanisms underlying their regulation. To accomplish this objective, we have formulated the following three specific aims: i) To characterize candidate virulence factors controlled by the Rrp2 pathway. ii) To determine the role of Hk2 in Rrp2 activation during tick transmission and mammalian infection. We will test the hypothesis that Hk2 is important to Rrp2 activation in vivo and to the infectious cycle of Bb. iii) To better define the signaling sensing mechanisms for the Hk2-dependent and Hk2-independent pathways for activation of Rrp2 in vivo and in vitro. We will test the hypothesis that the PAS domain of Hk2 is the receptor for mammalian host-specific signals, whereas acetyl-P is one of the factors that contribute to the Hk2-independent Rrp2 activation in vitro and in vivo. PUBLIC HEALTH RELEVACE Accomplishing Specific Aim 1 will identify new virulence factors that are important to mammalian infection. Outcomes of Aims 2 and 3 will elucidate the complex signal sensing mechanisms of the Rrp2 pathway, which will fill a major gap in our understanding of Bb host adaptation. These findings could lead to the developments of therapeutic targets and form a basis for developing strategies to block the enzootic cycle of Bb. The proposed work will also allow us to gain insight into host adaptation of other vector-borne bacterial pathogens.