Virulence regulation by BadR in the Lyme disease spirochete

BadR 对莱姆病螺旋体的毒力调节

• 批准号: 10376875
• 负责人: Zhiming Ouyang
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-24 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376875
• 关键词: Address; Arthropods; Bacteria; Bacteria sigma factor KatF protein; Binding; Biochemical; Biological; Borrelia burgdorferi; Borrelia oxidative stress regulator; Candidate Disease Gene; Chromosomes; Complex; Coupled; Data; Defect; Development; Disease; Etiology; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Growth; Homologous Gene; In Vitro; Infection; Intervention; Ixodes; Knowledge; Lead; Life Cycle Stages; Location; Lyme Disease; Maintenance; Mammals; Mediating; Modality; Molecular; Mus; Nature; Operon; Order Spirochaetales; Pathogenicity; Pathway interactions; Phase; Phenotype; Plasmids; Play; Promoter Regions; Proteins; Proteome; Regulation; Regulatory Pathway; Regulon; Role; Ticks; United States; Vector-transmitted infectious disease; Virulence; Work; antimicrobial; arthropod-borne; bacterial fitness; base; cohort; disorder prevention; enhancer binding protein; environmental adaptation; enzootic; expectation; imaging approach; in vivo; innovation; metabolome; mutant; novel; novel vaccines; outer surface lipoprotein; prevent; trait; transcriptome; transcriptome sequencing; transcriptomics; transmission process; vector; vector tick

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. Previously, we found that BadR, a homologue of ROK repressors, binds to the rpoS promoter region and represses the expression of rpoS. Moreover, our preliminary findings have suggested that BadR has much broader biological relevance to the life cycle of Bb other than repressing rpoS expression. First, BadR is required for Bb's optimal growth. Second, BadR plays a vital role in the establishment of mammalian infection. Contrary to the wild-type strain, a badR deletion mutant is incapable of infecting mice, suggesting that BadR governs expression of key effector proteins associated with Bb's survival in the host. Phenotypic defects of the badR mutant in mice infection are NOT related to the well documented RpoN-RpoS regulatory pathway, because all of BosR, Rrp2, RpoN, and RpoS are still produced in the badR mutant. In fact, our preliminary global transcriptomic analyses using RNA-seq have identified numerous BosR/RpoS-independent genes regulated by BadR. In addition, we found that badR is expressed throughout Bb's tick-mammal infectious cycle. These combined data give rise to our hypothesis that BadR is a master regulator governing Bb's host adaption and virulence expression. This hypothesis will be addressed in two Specific Aims. In Aim 1 of this proposal, we will employ global transcriptome/proteome profiling to define the entire BadR regulon under various in vitro and in vivo conditions. In Aim 2, we will select BadR-regulated genes based on our global transcriptome/proteome analyses and characterize their contributions to Bb's infectious cycle. These combined studies will (i) refine our knowledge on BadR-mediated gene regulation; (ii) provide a transformative understanding of the in vivo importance of the regulon; and (iii) identify novel virulence determinants. Resultant findings could lead to the development of new strategies to prevent and/or treat Lyme disease.

摘要 伯氏疏螺旋体是莱姆病的病原体，通过复杂的生活史维持在自然界中。 涉及节肢动物(扁虱)媒介和小型哺乳动物。在扁虱和哺乳动物之间的循环中，Bb 经历了戏剧性的适应性变化，以便与这两个不同的利基市场互动和适应。 此前，我们发现韩国抑制物的同源物BadR与rpos启动子区域结合，并 抑制rpos的表达。此外，我们的初步发现表明，巴德尔有很多 除了抑制rpos的表达外，还与BB的生命周期具有更广泛的生物学相关性。首先，Badr是必填项 为了BB的最佳增长。其次，Badr在哺乳动物感染的建立中起着至关重要的作用。相反的 对于野生型菌株，Badr缺失突变体不能感染小鼠，这表明Badr控制着 与BB在宿主中存活相关的关键效应蛋白的表达。Badr的表型缺陷 小鼠感染中的突变与已知的RpoN-rpos调控途径无关，因为所有 在BadR突变体中仍产生BosR、RRP2、RpoN和Rpos。事实上，我们初步的全球 使用rna-seq的转录分析已经确定了许多不依赖BosR/rpos的基因，这些基因受 巴德尔。此外，我们还发现Badr在Bb的森林-哺乳动物感染循环中都有表达。这些 综合数据得出我们的假设，即Badr是管理BB寄主适应和 毒力表达。这一假设将在两个具体目标中得到解决。在本提案的目标1中，我们将 利用整体转录组/蛋白质组图谱来确定在不同的体外和体外培养条件下的整个BadR调节子 活体条件。在目标2中，我们将根据我们的全球转录组/蛋白质组来选择Badr调节的基因 分析和描述它们对BB感染循环的贡献。这些综合研究将(I)完善我们的 了解BADR介导的基因调控；(Ii)提供对体内基因调控的变革性理解 调节子的重要性；以及(Iii)识别新的毒力决定因素。由此产生的发现可能导致 开发预防和/或治疗莱姆病的新策略。