Host adaptation of the Lyme disease spirochete

莱姆病螺旋体的宿主适应

• 批准号: 9257279
• 负责人: X. Frank Yang
• 金额: $ 40.99万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257279
• 关键词: Acetylation; Arthropod Vectors; Arthropods; Bacteria; Bacteria sigma factor KatF protein; Bacterial Proteins; Borrelia burgdorferi; Borrelia oxidative stress regulator; Complex; Cues; Disease; Environment; Foundations; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Infection; Ixodes; Libraries; Lyme Disease; Membrane Proteins; Metabolic; Metabolism; Nutrient; Nymph; Order Spirochaetales; Outcome; Pathogenesis; Pathway interactions; Phosphorylation; Physiology; Play; Process; Production; Protein Acetylation; Public Health; Regulation; Regulatory Pathway; Rodent; Role; Scientist; Second Messenger Systems; Shapes; Sigma Factor; Signal Transduction; Testing; Tick-Borne Diseases; Ticks; Tissue-Specific Gene Expression; United States; Virulence; Virulence Factors; Work; Yang; c new; enhancer binding protein; enzootic; experience; feeding; human disease; innovation; insight; novel; pathogen; public health relevance; response; transmission process; vector

 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.

 描述（由申请人提供）：莱姆病是美国的一个重要公共卫生问题，这种新出现的疾病诊断不足，并且莱姆病的晚期阶段很难治疗，其病原体伯氏疏螺旋体（Bb）维持在复杂的环境中。在地方性流行病周期中，其节肢动物载体（硬蜱）和涉及哺乳动物宿主的啮齿动物 Bb 必须显着改变其表面蛋白，以适应两种明显不同的宿主环境。此前，我们和其他人已经确定 RpoN-RpoS 途径是螺旋体地方性动物流行周期中差异基因表达的主要机制。该应用的目标是填补对这一基本途径的理解的主要空白。 ，即多个信号和调节器如何协调激活/调节该途径。我们的初步研究结果支持以下假设，这些假设将在三个具体目标中进行测试：1）该途径连接 Bb 代谢和毒力。乙酰化在该途径的激活和 Bb 的地方性动物循环中发挥重要作用。 3) 第二信使 c-di-GMP 通过新的 c-di-GMP 效应子调节该途径。这是一个包括四个经验丰富的合作项目。具有 Bb 基因调控（Yang；PI）、细菌乙酰化（Wolfe）、Bb 生理学（Gherardini）和 c-di-GMP（Gomelsky）方面专业知识的科学家。这项工作将揭示 Bb 如何进化以连接代谢和毒力，以及乙酰化如何在 Bb 的地方性循环中调节差异基因表达。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。该提案将填补我们对 Bb 如何适应节肢动物和哺乳动物宿主的理解的重大空白。这项工作的成果也将为制定阻止 Bb 的地方性动物循环的策略奠定基础，从而限制其。导致人类疾病的能力。