Virulence-associated genes in the Lyme disease spirochete

莱姆病螺旋体中的毒力相关基因

• 批准号: 9805771
• 负责人: Zhiming Ouyang
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-19 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805771
• 关键词: Address; Animals; Arthritis; Arthropods; Bacteria; Bacteria sigma factor KatF protein; Bacterial Infections; Biological Models; Borrelia; Borrelia burgdorferi; Borrelia oxidative stress regulator; Candidate Disease Gene; Carditis; Chromosomes; Clinical; Complex; Data; Development; Disease; Disease Progression; Environment; Essential Genes; Etiology; Europe; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Glean; Goals; Homologous Gene; Imaging Techniques; Infection; Inflammatory; Kinetics; Knowledge; Lead; Life Cycle Stages; Lipoproteins; Location; Lyme Disease; Mammals; Medical; Membrane; Midgut; Modality; Molecular; Mutagenesis; Nature; North America; OspC protein; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Phase; Physiology; Plasmids; Play; Prevention; Proteins; Regulatory Pathway; Research; Role; Sigma Factor; Ticks; United States; Vector-transmitted infectious disease; Virulence; Virulence Factors; Work; antimicrobial; bacterial fitness; base; decorin binding protein B; defined contribution; disorder prevention; enhancer binding protein; enzootic; expectation; fitness; gene function; in vivo; in vivo imaging; innovation; insight; interest; mouse model; mutant; novel; outer surface lipoprotein; prevent; transcriptome; transcriptome sequencing; vector; virtual

Abstract Borrelia burgdorferi (Bb), the etiological agent of Lyme disease, maintains itself in nature via a complex life cycle involving an arthropod (tick) vector and small mammals. During its cycle between ticks and mammals, Bb undergoes dramatic adaptive changes in order to interact with and adapt to these two disparate niches. A substantial number of studies have indicated that the RpoN-RpoS regulatory pathway (aka the σ54-σS cascade) plays a central role in host adaptation and virulence gene expression in Bb. Specifically, this pathway controls expression of major virulence-associated outer membrane lipoproteins including OspC, DbpA, and DbpB. Recently, we found that, in addition to the bacterial enhancer binding protein Rrp2, a Fur/PerR homologue called BosR is also required for the activation of the RpoN-RpoS pathway. More importantly, an overwhelming body of evidence supports that the BosR/RpoN/RpoS network governs expression of additional effector proteins associated with Bb fitness, survival, and pathogenesis. We performed global transcriptome profiling using microarray and RNA-seq and have identified potential BosR/RpoN/RpoS-regulated genes (other than ospC, dbpA and dbpB). However, virtually nothing is known regarding the functions and contributions of these genes to the tick-mammal infectious life cycle of Bb. In this proposal, we will directly examine the impact of two BosR/RpoN/RpoS-regulated genes on Bb's parasitic strategies. In Specific Aim 1, we shall systematically examine gene expression in Bb's native tick and mammal environments, which will pinpoint the potential life- cycle-specific roles of the gene targets. In Specific Aim 2, we shall define the roles of these genes in bacterial pathogenesis via genetic mutagenesis approaches and a Lyme borreliosis tick-mouse model system. Accomplishing the two Specific Aims of this proposal will advance our understanding of virulence expression control in Bb, and lead to the identification of new virulence factors. Defining the contributions of BosR/RpoN/RpoS-regulated genes to borrelial physiology and pathogenesis, and the mechanistic details underlying the respective gene functions, will be the focus of our future research, which may ultimately lead to the development of new strategies to prevent and/or treat Lyme disease.

抽象的 伯氏疏螺旋体 (Bb) 是莱姆病的病原体，通过复杂的生命周期在自然界中维持自身 节肢动物（蜱）媒介和小型哺乳动物 在蜱之间循环并涉及哺乳动物时，Bb。 为了与这两个不同的生态位互动并适应，经历了巨大的适应性变化。 大量研究表明 RpoN-RpoS 调控途径（又名 σ54-σS 级联） 在 Bb 中，该途径在宿主适应和毒力基因表达中发挥着核心作用。 主要毒力相关外膜脂蛋白（包括 OspC、DbpA 和 DbpB）的表达。 最近，我们发现，除了细菌增强子结合蛋白 Rrp2 之外，还有一个名为 Fur/PerR 同源物 BosR 也是 RpoN-RpoS 途径激活所必需的。 有证据表明 BosR/RpoN/RpoS 网络控制其他效应蛋白的表达 我们使用 Bb 适应性、存活率和发病机制进行了全局转录组分析。 微阵列和 RNA-seq 并鉴定了潜在的 BosR/RpoN/RpoS 调节基因（除了 ospC、 dbpA 和 dbpB) 然而，实际上对这些基因的功能和贡献一无所知。 在本提案中，我们将直接研究两个因素对蜱类哺乳动物传染性生命周期的影响。 BosR/RpoN/RpoS 调控基因对 Bb 寄生策略的影响 在具体目标 1 中，我们将系统地研究 Bb 的寄生策略。 检查 Bb 原生蜱和哺乳动物环境中的基因表达，这将查明潜在的生命- 在具体目标 2 中，我们将定义这些基因在细菌中的作用。 通过基因突变方法和莱姆疏螺旋体病蜱鼠模型系统确定发病机制。 实现该提案的两个具体目标将增进我们对毒力表达的理解 Bb 中的控制，并导致确定新的毒力因子的贡献。 BosR/RpoN/RpoS 调节基因对疏螺旋体生理学和发病机制的影响及其机制细节 各自基因功能的基础，将是我们未来研究的重点，这可能最终导致 制定预防和/或治疗莱姆病的新策略。