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。B。burgdorferi维持在涉及其节肢动物载体（硬蜱属蜱）和啮齿类哺乳动物宿主的复杂的地方流行循环中。关于B. burgdorferi适应两种截然不同的宿主环境并引起疾病。我们的长期目标是阐明宿主适应B的分子机制。burgdorferi的期望，这项工作将奠定基础的创新方法，用于治疗和预防莱姆病的发展。在这方面，我们已经确定了一个关键的调节Rrp2是必不可少的差异基因表达在螺旋体的地方流行周期。然而，激活Rrp2的上游信号通路仍然未知。在这个提议中，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，我们将确定的贡献乙酰磷酸和假定的组氨酸激酶的Rrp2激活。在第二个目标中，我们将研究ospAB突变体组成性激活Rrp2通路的分子机制。 公共卫生相关性：该提案的结果将阐明Rrp2通路的复杂信号感应机制，这将填补我们对Bb宿主适应的理解中的一个主要空白。这些发现可能会导致治疗靶点的发展，并为制定阻断Bb地方性流行周期的策略奠定基础。

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.