Bpur, a critical regulator of Borrelia burgdorferi infectivity

Bpur，伯氏疏螺旋体感染性的关键调节因子

• 批准号: 9220718
• 负责人: Brian Stevenson
• 金额: $ 18.53万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-10 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220718
• 关键词: Affect; Antibiotics; Arthropods; Bacteria; Bacterial Infections; Binding; Borrelia; Borrelia burgdorferi; DNA; DNA Sequence; Data; Engineering; Enzymes; Genes; Genetic Engineering; Genetic Transcription; Glycine; Human; Impairment; Infection; Link; Location; Lyme Disease; Mammals; Metabolic; Modeling; Mus; Mutate; Names; North America; Operon; Organism; Patients; Process; Production; Protein Biosynthesis; Proteins; RNA Sequences; RNA-Binding Proteins; Regulation; Regulatory Pathway; Site; Testing; Ticks; Transcriptional Regulation; Transfer RNA; Virulence Factors; design; human disease; mutant; novel; novel therapeutics; pathogen; public health relevance; transcriptome sequencing; transcriptomics; vector

 DESCRIPTION (provided by applicant): All organisms, from bacteria to humans, need to "recognize" where they are, and respond accordingly. A pathogen must sense its location in the infectious cycle, then produce factors necessary for that site while repressing synthesis of inappropriate factors. Thus, disruption of key regulatory pathways can inhibit a pathogen's ability to infect, indicating useful targets for developing novel antibiotics. In our studies of th Lyme disease bacterium, Borrelia burgdorferi, we discovered that regulation of a new DNA/RNA-binding protein named BpuR is required for mammalian infection. B. burgdorferi regulates production of BpuR, synthesizing it at low levels during mammalian infection processes, and at high levels during colonization of vector ticks. We genetically engineered B. burgdorferi to constitutively produce high levels of BpuR during murine infection, and found the mutant to be significantly impaired in its ability to colonize mice. Transcriptomic analyses (RNA-Seq) demonstrated that BpuR significantly affects expression of approximately 5% of B. burgdorferi operons, disturbing cellular levels of several known virulence factors and metabolic enzymes. We hypothesize that disruption of the processes controlling production of BpuR will significantly inhibit B. burgdorferi infection. The planned studies are designed to elucidate the mechanism by which B. burgdorferi controls expression of this critical regulatory factor, and determine how disrupting that mechanism impacts upon infection processes.

 描述（由申请人提供）：所有生物体，从细菌到人类，都需要“识别”它们所在的位置，并做出相应的反应。病原体必须感觉到它在感染循环中的位置，然后产生该位点所需的因子，同时抑制不适当因子的合成。因此，关键调控途径的破坏可以抑制病原体的感染能力，这表明了开发新型抗生素的有用靶点。在我们对莱姆病细菌伯氏疏螺旋体的研究中，我们发现哺乳动物感染需要一种新的DNA/RNA结合蛋白BpuR的调节。B。burgdorferi调节BpuR的产生，在哺乳动物感染过程中以低水平合成，在媒介蜱定殖期间以高水平合成。我们对B进行了基因改造。Burgdorferi的研究表明，在小鼠感染期间，突变体组成性地产生高水平的BpuR，并且发现突变体在其定殖小鼠的能力方面显著受损。转录组学分析（RNA-Seq）证明BpuR显著影响约5%的B的表达。burgdorferi操纵子，干扰几种已知毒力因子和代谢酶的细胞水平。我们假设，控制BpuR产生的过程的中断将显著抑制B。伯氏感染计划的研究旨在阐明B. burgdorferi控制着这一关键调节因子的表达，并确定了破坏该机制如何影响感染过程。