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

描述（由申请人提供）： 莱姆病是美国最常见的病媒传播疾病。病原体伯氏疏螺旋体（Bb）通过涉及蜱和哺乳动物宿主的复杂的地方病循环维持。因此，螺旋体必须适应这两种截然不同的宿主并在其中生存。在沉积在皮肤中后，螺旋体然后通过皮肤传播到血液中并定殖于其他器官，并引起通常涉及皮肤、关节、心脏和神经系统的许多临床症状。在美国，该病的主要表现之一是莱姆关节炎。Bb螺旋体最有趣的特点是，在其生命周期和疾病发展过程中，该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。这种能力不仅是螺旋体适应和在不同宿主中生长的关键，而且在螺旋体致病中起着非常重要的作用。显然，Bb发展了复杂的调节系统来感知环境变化，并相应地操纵这种遗传适应。然而，只有少数监管系统已被确定在BB。 双组分系统是细菌对外部和内部信号应答中最常见的信号转导途径。一些细胞过程由双组分系统调节，包括毒力基因控制、宿主适应、孢子形成、芽孢调节和趋化性。在这个建议中，我们假设，细菌的双组分系统HK 1-RR 1在基因调控，哺乳动物感染和载体传播的Bb的发病机制中起着非常重要的作用。这些假设将通过几种方法进行测试，包括生物化学，遗传学，基因组和蛋白质组学测定以及莱姆病小鼠模型和小鼠蜱感染研究。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。这些结果可能会导致疾病预防和治疗的新方法。 莱姆病是美国最常见的蜱传疾病，由伯氏疏螺旋体引起。宿主适应在该病的发病过程中起着重要作用。本项目的目标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。所获得的结果可能导致疾病预防和治疗的新手段。

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.