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

伯氏疏螺旋体Rrp2-RpoN-RpoS通路的激活机制

• 批准号: 7773498
• 负责人: X. Frank Yang
• 金额: $ 18.07万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7773498
• 关键词: Affect; Arthropod Vectors; Arthropods; Bacteria sigma factor KatF protein; Biochemical; Borrelia burgdorferi; Cardiac; Complex; Data; Dermatologic; Development; Disease; Environment; Gene Expression; Generations; Genes; Genetic; Genome; Goals; Infection; Invaded; Ixodes; Lead; Length; Lipoproteins; Lyme Disease; Mammals; Modeling; Molecular; Molecular Profiling; Neurologic; Nymph; Order Spirochaetales; OspA protein; Outcome; Pathway interactions; Peptide Signal Sequences; Play; Prevention; Production; Regulation; Regulatory Pathway; Repression; Research; Rodent; Role; Sigma Factor; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Surface; Temperature; Testing; Ticks; Tissue-Specific Gene Expression; Variant; Work; acetyl phosphate; base; enzootic; expectation; feeding; innovation; inorganic phosphate; mutant; novel; protein-histidine kinase; public health relevance; response; therapeutic target; tool; transmission process

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.

描述（由申请人提供）：莱姆病由节肢动物传播的螺旋体伯氏疏螺旋体引起，是一种多系统疾病，可导致皮肤病、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动物循环中，涉及其节肢动物载体（硬蜱）和啮齿类哺乳动物宿主。人们对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，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调节因子 Rrp2，它对于螺旋体地方性动物流行周期中差异基因表达至关重要。然而，激活 Rrp2 的上游信号通路仍然未知。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 途径激活的信号通路。第一个目标是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 突变体组成型激活 Rrp2 通路的分子机制。 公共健康相关性：该提案的结果将阐明 Rrp2 途径的复杂信号传感机制，这将填补我们对 Bb 宿主适应理解的重大空白。这些发现可能会导致治疗靶点的开发，并为制定阻止 Bb 地方性动物循环的策略奠定基础。