Host adaptation of the Lyme disease spirochete

 描述(申请人提供)：莱姆病是美国一个重要的公共卫生问题。这种新出现的疾病被低估了，莱姆病的晚期很难治疗。伯氏疏螺旋体是由其节肢动物媒介(硬蜱)和啮齿类哺乳动物宿主组成的一个复杂的地方病循环。为了适应两种截然不同的寄主环境，取食扁虱时，Bb必须戏剧性地改变其表面蛋白。此前，我们和其他人已经证实，RpoN-rpos途径在螺旋体的流行周期中是导致差异基因表达的主要机制。这一应用的目的是填补对这一重要途径的理解的主要空白，即多个信号和调节因子如何协调激活/调节这一途径。我们的初步发现支持以下假说，这些假说将在三个特定的目标中得到验证：1)该途径连接BB代谢和毒力。2)乙酰化在该途径的激活和BB的流行循环中起着重要作用。3)第二信使c-di-GMP通过一个新的c-di-GMP效应器调节这一途径。这是一个合作项目，包括四位经验丰富的科学家，他们在BB基因调控(Yang；Pi)、细菌乙酰化(Wolfe)、BB生理学(Gherardini)和c-di-GMP(Gomelsky)方面具有专业知识。这项工作的结果将揭示BB是如何进化来连接新陈代谢和毒力的，以及乙酰化如何在BB的地方性循环中调节差异基因的表达。这项工作还将揭示c-di-GMP在媒介传播病原体的宿主适应中的新作用。我们的建议将填补我们在理解BB如何适应节肢动物和哺乳动物宿主方面的一个主要空白。这项工作的结果还将为制定阻断BB地方性循环的战略奠定基础，从而限制其导致人类疾病的能力。

 DESCRIPTION (provided by applicant): Lyme disease is an important public health problem in the US. This emerging disease is underdiagnosed, and the late stages of Lyme disease are difficult to treat. The causative agent Borrelia burgdorferi (Bb) is maintained in a complex enzootic cycle involving its arthropod vector (Ixodes ticks) and a rodent mammalian host. Bb must dramatic alters its surface proteins in order to adapt to two markedly different host environments during tick feeding. Previously, we and others have established that the RpoN-RpoS pathway functions as a major mechanism underlying differential gene expression during the spirochete's enzootic cycle. The goal of this application is to fill in the major gap in the understanding of this essential pathway, that is, how multiple signals and regulators coordinately activate / regulate this pathway. Our preliminary findings support the following hypotheses, which will be tested in three Specific Aims: 1) This pathway connects Bb metabolism and virulence. 2) Acetylation plays an important role in the activation of this pathway and in the enzootic cycle of Bb. 3) the second messenger c-di-GMP modulates this pathway via a new c-di-GMP effector. This is a collaborative project including four experienced scientists with expertise in Bb gene regulation (Yang; PI), bacterial acetylation (Wolfe), Bb physiology (Gherardini), and c-di-GMP (Gomelsky). Outcomes of the work will reveal how Bb has evolved to connect metabolism and virulence and how acetylation modulates differential gene expression during the enzootic cycle of Bb. This work will also reveal a novel role of c-di-GMP in host adaptation of vector-borne pathogens. Our proposal will fill a major gap in our understanding of how Bb adapts to both arthropod and mammalian hosts. Outcomes of this work also will set a foundation for developing strategies to block the enzootic cycle of Bb, thus limiting its ability to cause human disease.