Redox Regulation of DksA-dependent Borrelia burgdorferi infectivity

DksA 依赖性伯氏疏螺旋体感染性的氧化还原调节

• 批准号: 10585293
• 负责人: Travis J Bourret
• 金额: $ 42.45万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585293
• 关键词: Antioxidants; Area; Binding; Biology; Black-legged Tick; Borrelia burgdorferi; Coupled; Cysteine; DNA-Directed RNA Polymerase; Data; Development; Diagnosis; Environment; Etiology; Exposure to; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; In Vitro; Infection; Ixodes; Knowledge; Label; Laboratories; Lyme Disease; Maps; Metabolism; Modeling; Modification; Molecular; Molecular Genetics; Monitor; Mus; Mutation; Nitric Oxide; Nitrogen Dioxide; Nutrient; Nutrient availability; Order Spirochaetales; Osmolar Concentration; Osmosis; Oxidants; Oxidation-Reduction; Pathogenesis; Positioning Attribute; Prevalence; Protein Array; Proteins; Proteomics; Public Health; Publishing; Reactive Nitrogen Species; Reactive Oxygen Species; Regulation; Regulator Genes; Research; Role; Site; Source; Stress; Sulfhydryl Compounds; System; Temperature; Testing; Tick-Borne Diseases; Tick-Borne Infections; Ticks; United States; Work; Zinc; Zinc Fingers; combat; environmental stressor; enzootic; genetic manipulation; genetic regulatory protein; genetic variant; innovation; insight; novel; oxidation; prevent; response; sensor; tick-borne; tool; transmission process; vector; vector tick; vector-borne pathogen; virtual; virulence gene

PROJECT SUMMARY Borrelia burgdorferi, the etiologic agent of Lyme disease, is a major source of illness in the United States with over 476,000 cases per year. Like other vector-borne pathogens, B. burgdorferi must overcome a wide variety of environmental stresses during its infectious cycle in ticks of the genus Ixodes, and various mammalian hosts. Among the challenges faced by B. burgdorferi are shifts in pH, temperature, osmolarity, nutrient availability, reactive oxygen species (ROS) along with nitric oxide (NO) and its congeners [reactive nitrogen species (RNS) (e.g., NO, NO2•, N2O3 and ONOO-)]. Of these, the roles of temperature and pH on B. burgdorferi virulence gene expression and infectivity have been the best characterized. Previously published work from our laboratory and others have demonstrated that B. burgdorferi encounters biologically significant amounts of ROS and RNS during infection of its tick vector Ixodes scapularis and mammalian hosts. We have also shown that cysteine thiols of proteins involved in gene regulation, antioxidant defenses, and central metabolism are targets of ROS and RNS, although the impact of these modifications on B. burgdorferi infectivity have yet to be determined. Our previously published work showed the DnaK suppressor protein (DksA) is a global regulator of gene expression in B. burgdorferi and coordinates the stringent response during periods of nutrient limitation. We now have preliminary data supporting a role for DksA in regulating virulence gene expression required for completion of its infectious cycle in I. scapularis and mammalian hosts. Despite this, there are substantial gaps in our knowledge about how DksA senses changes within its vector and mammalian hosts to direct B. burgdorferi gene expression. In this application, we propose to test our central hypothesis that DksA senses tick-borne ROS/RNS to coordinate the transcriptional responses of B. burgdorferi required for the completion of its infectious cycle. This proposal is particularly innovative and will impact the field of tick-borne diseases by determining the mechanisms underlying the ability of B. burgdorferi to sense changes in its environment to regulate gene expression. Since this area of research is virtually uninvestigated for tick-borne diseases, our findings will undoubtedly provide insight to the field and inform future strategies to prevent tick-borne infections.

项目概要 伯氏疏螺旋体是莱姆病的病原体，是美国的主要疾病来源 与其他媒介传播的病原体一样，伯氏疏螺旋体每年有超过 476,000 例病例。 硬蜱属蜱和各种哺乳动物宿主的感染周期中环境应激的影响。 伯氏疏螺旋体面临的挑战包括 pH 值、温度、渗透压、营养可用性的变化， 活性氧 (ROS) 以及一氧化氮 (NO) 及其同系物 [活性氮 (RNS) （例如，NO、NO2•、N2O3 和 ONOO-）] 其中，温度和 pH 对伯氏疏螺旋体毒力基因的作用。 表达和感染性是我们实验室之前发表的工作的最好特征。 其他人已经证明伯氏疏螺旋体遇到了具有生物学意义的大量 ROS 和 RNS 在其蜱载体肩突硬蜱和哺乳动物宿主的感染过程中，我们还发现了半胱氨酸。 参与基因调控、抗氧化防御和中枢代谢的蛋白质硫醇是 ROS 的目标 和 RNS，尽管这些修饰对伯氏疏螺旋体感染性的影响尚未确定。 之前发表的研究表明 DnaK 抑制蛋白 (DksA) 是基因表达的全局调节因子 伯氏疏螺旋体并协调营养限制期间的严格反应。 初步数据支持 DksA 在调节完成其毒力基因表达所需的毒力基因表达中的作用 尽管如此，我们的知识仍然存在很大差距。 关于 DksA 如何感知其载体和哺乳动物宿主内的变化以指导伯氏疏螺旋体基因表达。 在此应用中，我们建议测试我们的中心假设，即 DksA 感知蜱传 ROS/RNS 来协调 伯氏疏螺旋体完成其感染周期所需的转录反应。 特别具有创新性，将通过确定根本机制来影响蜱传疾病领域 伯氏疏螺旋体感知环境变化以调节基因表达的能力。 对于蜱传疾病的研究实际上尚未进行调查，我们的研究结果无疑将为我们提供深入的见解 领域并为未来预防蜱传感染的策略提供信息。