Regulation of Host-adaptation of the Lyme disease Spirochete Borrelia burgdorferi

描述(申请人提供)：莱姆病是美国最常见的媒介传播疾病。伯氏疏螺旋体(BB)的致病因子通过一种复杂的地方性循环而得以维持，这种地方性循环涉及到扁虱和哺乳动物宿主。因此，螺旋体必须适应这两个截然不同的宿主并在其中生存。在皮肤中沉积后，螺旋体通过皮肤传播到血液中，并在其他器官定居，引起许多临床症状，通常涉及皮肤、关节、心脏和神经系统。在美国，这种疾病的主要表现之一是莱姆关节炎。BB最耐人寻味的特征是，在其生活史和疾病发展过程中，这种螺旋体可以在不同的宿主、不同的时间甚至在不同的微环境中优先表达选定的基因。这种能力不仅对螺旋体适应和在不同宿主中茁壮成长至关重要，而且在螺旋体的致病过程中也起着非常重要的作用。显然，BB开发了复杂的调控系统来感知环境变化，并相应地操纵这种遗传适应。然而，在BB中只发现了几个监管系统。 在细菌对外部和内部信号的反应中，双组分系统是最常见的信号转导途径。一些细胞过程受双组分系统的调控，包括毒力基因控制、寄主适应、孢子形成、渗透调节和趋化作用。在这一建议中，我们假设一个细菌二组分系统HK1-RR1在BB的基因调控、哺乳动物感染和媒介传播方面发挥着非常重要的作用。这些假说将通过几种方法进行验证，包括生化、遗传、基因组和蛋白质组分析，以及莱姆病的小鼠模型和鼠虱感染研究。本项目获得的数据将有助于我们了解BB在其生命周期中如何调节其遗传适应，以及这种遗传适应在哺乳动物感染和媒介传播中的作用。这一结果可能会带来新的疾病预防和治疗手段。 莱姆病是美国最常见的扁虱传播疾病，由伯氏疏螺旋体引起。宿主适应在该病中起着非常重要的作用。本项目的目的是研究螺旋体如何通过细菌双组分信号通路调节宿主适应及其在螺旋体致病中的作用。这一结果可能为疾病的防治提供新的手段。

DESCRIPTION (provided by applicant): Lyme disease is the most common vector-borne disease in the United State. The causative agent Borrelia burgdorferi (Bb) is maintained through a complex enzootic cycle involving in tick and mammalian hosts. Consequently, the spirochete has to adapt to and survive in these two dramatically different hosts. After being deposited in the skin, the spirochetes then disseminate through the skin into the blood and colonize other organs and cause numerous clinical symptoms that commonly involve the skin, joints, heart and nervous system. In the United States, one of the major manifestations of the disease is Lyme arthritis. The most intriguing feature of Bb is that this spirochete can preferentially express selected genes in the different hosts, at different times, and even in different microenvironments during its life cycle and the disease development. This ability is not only critical for the spirochete to adapt to and thrive in the different hosts but also plays very important roles in the spirochete pathogenesis. Clearly, Bb developed complex regulatory systems to sense environmental changes and correspondingly manipulate such genetic adaptation. However, only a few regulatory systems have been identified in Bb. Two-component systems are the most common signaling transduction pathways in the response of bacteria to both external and internal signals. Several cellular processes are regulated by two-component systems, including virulence gene control, host-adaptations, sporulation, osmoregulation and chemotaxis. In this proposal, we hypothesize that a bacterial two-component system HK1-RR1 plays very important roles in the pathogenesis of Bb in terms of gene regulation, mammalian infection and vector transmission. Such hypotheses will be tested by several approaches, including biochemical, genetic, genomic and proteomic assays as well as a mouse model of Lyme disease and mouse-tick infection studies. The obtained data from this project will help us to understand how Bb regulates its genetic adaptation during its life cycle and the roles of such genetic adaptation in the mammalian infection and vector transmission. The results may lead to new means of disease prevention and treatment. Lyme disease is the most common tick-borne disease in the United States, which is caused by the spirochete Borrelia burgdorferi. Host adaptation plays very important roles in the disease. The goal of this project is to investigate how the spirochete regulates host adaptation through a bacterial two- component signaling pathway and its role in the spirochete pathogenesis. The obtained results may lead to new means of disease prevention and treatment.