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

描述（由申请人提供）：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、心脏、神经和风湿病表现。伯氏疏螺旋体维持在一个复杂的地方性循环中，涉及其节肢动物媒介（蜱虫）和啮齿动物哺乳动物宿主。对于伯氏疏螺旋体如何适应两种截然不同的宿主环境并引起疾病，人们知之甚少。我们的长期目标是阐明伯氏疏螺旋体宿主适应的分子机制，并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Rrp2，它是在螺旋体的地方性动物循环中差异基因表达所必需的。然而，激活Rrp2的上游信号通路尚不清楚。在本提案中，我们将采用温度诱导的Rrp2激活模型来剖析导致Rrp2通路激活的信号通路。在第一个目标中，我们将确定乙酰磷酸和假定的组氨酸激酶对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通路的分子机制。

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.