The mechanism of activation of the Rrp2-RpoN-RpoS pathway in Borrelia burgdorferi

描述(申请人提供)：莱姆病，由节肢动物传播的伯氏疏螺旋体引起，是一种多系统疾病，可导致皮肤病、心脏病、神经病和风湿病。伯氏假单胞菌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)和啮齿哺乳动物宿主。关于伯氏杆菌如何适应两种截然不同的寄主环境并导致疾病，人们知之甚少。我们的长期目标是阐明伯氏杆菌宿主适应的分子机制，期望这项工作将为开发治疗和预防莱姆病的创新方法奠定基础。在这方面，我们已经确定了一个关键的调控因子RRP2，它对于螺旋体的地方性循环中的差异基因表达是必不可少的。然而，激活RRP2的上游信号通路仍不清楚。在这个方案中，我们将使用温度诱导的RRP2激活模型来剖析导致RRP2途径激活的信号通路。在第一个目标中，我们将确定乙酰磷酸和可能的组氨酸激酶对RRP2激活的贡献。在第二个目标中，我们将研究OspAB突变体激活RRP2途径的分子机制。 与公共健康相关：这项提议的结果将阐明RRP2途径的复杂信号传感机制，这将填补我们对BB宿主适应的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。

DESCRIPTION (provided by applicant): Lyme disease, caused by the arthropod-borne spirochete Borrelia burgdorferi, is a multisystem disorder that can lead to dermatologic, cardiac, neurologic, and rheumatologic manifestations. B. burgdorferi is maintained in a complex enzootic cycle involving its arthropod vector (Ixodes ticks) and a rodent mammalian host. Little is known about how B. burgdorferi adapts to two such distinctly different host environments and causes disease. Our long-term objective is to elucidate molecular mechanisms underlying host adaptation of B. burgdorferi with the expectation that this work will lay the groundwork for the development of innovative approaches for the treatment of and prevention of Lyme disease. In this regard, we have identified a key regulator Rrp2 that is essential for differential gene expression during the spirochete's enzootic cycle. However, the upstream signaling pathway that activates Rrp2 remains unknown. In this proposal, we will employ the temperature-induced Rrp2 activation model to dissect the signaling pathway that leads to the activation of the Rrp2 pathway. In the first aim, we will determine the contributions of acetyl phosphate and the putative histidine kinases to the Rrp2 activation. In the second aim, we will investigate the molecular mechanism underlying constitutive activation of the Rrp2 pathway by the ospAB mutant. PUBLIC HEALTH RELEVANCE: Outcomes of this proposal 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.