Host adaptation of the Lyme disease spirochete

描述(申请人提供)：伯氏疏螺旋体(BB)，莱姆病的病原体，维持在一个复杂的地方病循环中，涉及其节肢动物媒介(硬蜱)和啮齿动物哺乳动物宿主。Bb进化为适应两种明显不同的寄主环境的关键策略是其表面蛋白在取食过程中的戏剧性变化。在过去的几年里，我们和其他人发现了一个新的调控途径，RRP2-RpoN-rpos途径(RRP2途径)，作为螺旋体地方性循环中差异基因表达的主要机制。RRP2途径的发现产生了两个基本问题，这两个问题对于我们理解BB对宿主的适应至关重要。(I)RRP2途径控制的毒力因子是什么？(Ii)激活RRP2途径的上游信号事件是什么？我们的长期目标是通过识别BB毒力因子并破译其调控机制来阐明BB如何致病。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RRP2途径控制的候选毒力因子。Ii)确定Hk2在硬蜱传播和哺乳动物感染过程中RRP2激活中的作用。我们将验证这一假设，即Hk2在体内对RRP2的激活和对BB的感染循环是重要的。Iii)更好地确定体内和体外激活RRP2的Hk2依赖和非Hk2途径的信号传感机制。我们将检验这一假设，即Hk2的PAS结构域是哺乳动物宿主特异性信号的受体，而乙酰基-P是在体外和体内促进Hk2非依赖性RRP2激活的因素之一。实现特定目标1的公共卫生RELEVACE将确定对哺乳动物感染重要的新毒力因子。AIMS 2和AIMS 3的结果将阐明RRP2途径的复杂信号传感机制，这将填补我们对BB宿主适应理解的一个主要空白。这些发现可能导致治疗靶点的发展，并为制定阻断BB地方性循环的策略奠定基础。拟议的工作还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情况。

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.