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.

摘要 莱姆病的病原体伯氏疏螺旋体（Borreliaburgdorferi，Bb）在自然界中通过复杂的生活史维持自身的生命 涉及节肢动物（蜱）媒介和小型哺乳动物。在蜱和哺乳动物之间的循环中，Bb 经历了戏剧性的适应性变化，以便与这两个截然不同的小生境相互作用并适应它们。一 大量研究表明，RpoN-RpoS调节途径（又名σ54-σS级联） 在Bb的寄主适应和毒力基因表达中起着重要作用。具体来说，这条途径控制着 表达主要的毒性相关外膜脂蛋白，包括OspC、DbpA和DbpB。 最近，我们发现，除了细菌增强子结合蛋白Rrp 2，一个Fur/PerR同源物，称为 BosR也是RpoN-RpoS通路激活所必需的。更重要的是， 证据支持BosR/RpoN/RpoS网络控制额外效应蛋白的表达 与Bb适应性、存活率和发病机制相关。我们使用 微阵列和RNA-seq，并且已经鉴定了潜在的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 与蜱哺乳动物感染性生命周期的关系在本建议中，我们将直接研究两个 BosR/RpoN/RpoS调节基因对Bb寄生策略的影响在具体目标1中，我们将系统地 检查Bb的原生蜱和哺乳动物环境中的基因表达，这将确定潜在的生命- 基因靶点的周期特异性作用。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研究发病机制。 实现这两个具体目标的建议将促进我们的理解毒力表达 控制Bb，并导致新的毒力因子的鉴定。界定捐助者的贡献 BosR/RpoN/RpoS调控基因对疏螺旋体生理和发病机制的影响及其机制细节 潜在的各自的基因功能，将是我们未来研究的重点，这可能最终导致 开发新的策略来预防和/或治疗莱姆病。