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.

抽象的 莱姆病的病因学剂Borrelia Burgdorferi（BB）通过复杂的生命周期维持自然界 涉及节肢动物（tick）载体和小型哺乳动物。在壁虱和哺乳动物之间的周期中，BB 经历了戏剧性的自适应变化，以与这两个不同的壁ni互动并适应这两个不同的壁ni。 以前，我们发现ROK阻遏物的同源物Badr与RPOS启动子区域结合，并且 抑制RPO的表达。而且，我们的初步发现表明，Badr有很多 除了抑制RPOS表达以外，与BB的生命周期更广泛的生物学相关性。首先，需要Badr 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 对于野生型菌株，BADR缺失突变体无法感染小鼠，这表明BADR控制 与BB在宿主中生存有关的关键效应蛋白的表达。 Badr的表型缺陷 小鼠感染中的突变体与记录良好的RPON-RPOS调节途径无关，因为所有 BOSR，RRP2，RPON和RPOS仍在BadR突变体中产生。实际上，我们的初步全球 使用RNA-SEQ进行转录组分析已鉴定出许多由BOSR/RPOS独立的基因 Badr。此外，我们发现BADR在整个BB的tick哺乳动物感染周期中都表现出来。这些 联合数据引起了我们的假设，即BADR是管理BB主机适应和 毒力表达。该假设将以两个具体目标解决。在本提案的目标1中，我们将 采用全局转录组/蛋白质组分析来定义整个BADR调节，并在各种体外和 体内条件。在AIM 2中，我们将根据我们的全局转录组/蛋白质组选择BADR调节的基因 分析和表征它们对BB传染性周期的贡献。这些合并的研究将（i）完善我们的 关于BADR介导的基因调节的知识； （ii）对体内的变革性理解 法规的重要性； （iii）确定新颖的毒力决定因素。结果可能会导致 制定预防和/或治疗莱姆病的新策略。