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.

项目摘要 莱姆病的病原体伯氏疏螺旋体是美国的主要疾病来源， 每年超过47.6万例。与其他媒介传播的病原体一样，B. burgdorferi必须克服各种各样的 在硬蜱属蜱和各种哺乳动物宿主的感染周期中的环境压力。 在B面临的挑战中。burgdorferi是pH值，温度，渗透压，营养可用性， 活性氧（ROS）沿着一氧化氮（NO）及其同类物[活性氮（RNS） (e.g., NO、NO2·、N2 O3和ONOO-）]。其中，温度和pH对B.莱姆病毒力基因 表达和感染力已经得到了最好的表征。我们实验室以前发表的工作， 其他人已经证明B. burgdorferi遇到生物学上显著量的ROS和RNS 在其蜱媒介肩突硬蜱和哺乳动物宿主的感染过程中。我们还发现半胱氨酸 参与基因调控、抗氧化防御和中枢代谢的蛋白质巯基是ROS的靶点 和RNS，尽管这些修改对B.伯氏螺旋体的传染性还有待确定。我们 先前发表的工作表明，DnaK抑制蛋白（DksA）是基因表达的全局调节因子 在B。burgdorferi和协调严格的响应期间的营养限制。我们现在有 初步数据支持DksA在调节完成其毒性基因表达所需的作用。 I.感染周期肩胛骨和哺乳动物宿主。尽管如此，我们的知识仍有很大差距， 关于DksA如何感知其载体和哺乳动物宿主内的变化来指导B。burgdorferi基因表达。 在这个应用中，我们提出测试我们的中心假设，即DksA感觉蜱传ROS/RNS协调 B的转录反应。完成其传染周期所需的时间。这项建议是 特别创新，并将通过确定潜在的机制来影响蜱传疾病领域。 B的能力burgdorferi感知环境的变化来调节基因的表达。由于这一领域的 研究几乎是未经调查的蜱传疾病，我们的研究结果无疑将提供洞察力， 实地考察并为今后预防蜱媒感染的战略提供信息。