SpoVG and PlzA Regulation of Lyme Disease Spirochete Infection Processes

SpoVG 和 PlzA 对莱姆病螺旋体感染过程的调节

• 批准号: 10597629
• 负责人: Brian Stevenson
• 金额: $ 69.78万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597629
• 关键词: Affect; Affinity; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antigenic Variation; Back; Bacteria; Bacterial Infections; Bacterial Physiology; Binding; Binding Proteins; Binding Sites; Biology; Borrelia; Borrelia burgdorferi; Cessation of life; ChIP-seq; Collaborations; Cues; DNA; DNA Binding; Data; Development; Environment; Failure; Gene Expression; Genes; Genetic Transcription; Genome; Homologous Gene; Human; Immunocompetent; Impairment; Infection; Infection Control; Infectious Agent; Invaded; Investigation; Joints; Knowledge; Laboratory Finding; Lyme Disease; Mammals; Maps; Mechanics; Membrane Proteins; Mus; Nature; North America; Order Spirochaetales; Organism; Pathogenesis; Pathogenicity; Patients; Periodicity; Physiology; Preventive therapy; Process; Production; Property; Proteins; Proteomics; RNA; RNA Sequences; RNA immunoprecipitation sequencing; RNA-Binding Proteins; Recording of previous events; Regulation; Regulatory Pathway; Regulon; Repression; Research Personnel; Role; Site; Specificity; Spirochaetales Infections; Ticks; Vertebrates; Virulence; Virulence Factors; Work; arthropod-borne; curative treatments; genetic regulatory protein; human disease; human pathogen; improved; insight; member; microbial; mutant; novel therapeutics; nucleic acid binding protein; pathogen; pathogenic bacteria; posttranscriptional; protein expression; response; stem; tick feeding; tick transmission; transcriptome; transcriptomics; transmission process; vector-borne pathogen

v ABSTRACT Bacterial infections require that the pathogen accurately produce essential factors at appropriate levels during each stage of infection processes. Understanding how bacteria control levels of their proteins in response to cues from their hosts provides important insights on microbial infectious properties. Such knowledge can also reveal new targets for improved preventative and curative therapies. The Lyme disease spirochete, Borrelia burgdorferi, survives in nature through cycles of infecting vertebrates and ticks. The CDC calculates that there are approximately 300,000 new cases of human Lyme disease in the USA each year. B. burgdorferi can persistently infect immunocompetent humans and other mammals for many years. Failure to treat Lyme disease promptly and adequately can result in persistent debilitating effects or, sometimes, death. Long-term infections may require extensive periods of antibiotic treatment. In order to better treat Lyme disease, it is critical to develop a more thorough understanding of B. burgdorferi biology, including the mechanisms by which the spirochete controls production of virulence factors. We discovered that a borrelial protein, SpoVG, binds with specificity and high affinity to DNA and RNA. Deletion of spoVG significantly impaired B. burgdorferi's ability to colonize ticks and be transmitted from ticks to mammals. Dysregulation of spoVG transcription caused significant changes in bacterial physiology. We further found that SpoVG directly interacts with another B. burgdorferi protein, PlzA, the Lyme spirochete's cyclic-di-GMP-binding protein. Our studies revealed that PlzA is also a site-specific nucleic acid-binding protein, and ΔplzA mutants are defective in their infectivity. Among the many regulated targets we identified for SpoVG and PlzA is the antigenically-variable VlsE surface protein, which is essential for persistent B. burgdorferi infection. The planned studies will simultaneously investigate SpoVG and PlzA, as well as the effects of c-di-GMP on their functions. These preliminary data stemmed from long-standing collaborations between the P.I. and co- investigators of this proposal. Our combined efforts will yield a comprehensive view of the mechanisms through which B. burgdorferi controls production of these critical regulatory factors, and deep insights on how SpoVG, PlzA, and c-di-GMP regulate VlsE and other virulence-associated proteins. In addition, many other pathogenic bacteria produce homologs of SpoVG, and our observations on B. burgdorferi SpoVG bear similarities with the protein's known effects in other bacterial pathogens. To date, little is known about how SpoVG affects virulence and physiology in any bacterial species. The interactions we discovered between SpoVG and PlzA raise the possibilities that other bacteria also control SpoVG function through c-di-GMP-binding proteins. Results of the planned investigations will provide useful insights on the regulatory mechanisms and infectious properties of numerous important human pathogens.

v摘要 细菌感染要求病原体在适当水平的情况下准确地产生基本因素 感染过程的每个阶段。了解细菌如何控制其蛋白质水平 宿主的提示提供了有关微生物感染特性的重要见解。这样的知识也可以 揭示了改善预防和治疗疗法的新靶标。 莱姆病螺旋体，伯氏伯氏菌，通过感染脊椎动物的周期在自然界中生存 和tick。 CDC计算出大约有300,000例新的人类莱姆病病例 每年美国。 B. Burgdorferi可以持续感染许多人的免疫能力人和其他哺乳动物 年。无法迅速而充分地治疗莱姆病，可能会导致持续的使人衰弱的影响或 有时候，死亡。长期感染可能需要大量的抗生素治疗。为了更好 治疗莱姆病，至关重要的是，对B. burgdorferi生物学有更透彻的了解，包括 螺旋体控制病毒因子的产生的机制。 我们发现，硼质蛋白SPOVG具有特异性和对DNA和RNA的高亲和力。 SPOVG的删除大大损害了B. Burgdorferi殖民tick并从tick虫传播的能力 致哺乳动物。 SPOVG转录的失调会导致细菌生理学的显着变化。我们 进一步发现，Spovg直接与另一个B. burgdorferi蛋白，PLZA，莱姆螺旋体的蛋白质相互作用 环状-DI-GMP结合蛋白。我们的研究表明，PLZA也是特定于现场的核酸结合 蛋白质和ΔPlza突变体在其感染中有缺陷。在我们确定的许多受监管的目标中 SPOVG和PLZA是抗原可变的VLSE表面蛋白，对于持续B。 伯格多菲利感染。 计划的研究将简单地研究SPOVG和PLZA，以及C-DI-GMP对 他们的功能。这些初步数据源于P.I.之间的长期合作。和共同 该提案的调查人员。我们的综合努力将通过 B. burgdorferi控制着这些关键调节因素的产生，并深入了解Spovg如何 PLZA和C-DI-GMP调节VLSE和其他与病毒相关的蛋白质。 此外，许多其他致病细菌产生了SPOVG的同源物，以及我们对B的观察结果。 Burgdorferi Spovg与蛋白质在其他细菌病原体中的已知作用具有相似性。迄今为止，很少 知道SPOVG如何影响任何细菌的病毒和生理。我们的互动 在SPOVG和PLZA之间发现了其他细菌也控制SPOVG功能的可能性 通过C-DI-GMP结合蛋白。计划调查的结果将为您提供有用的见解 许多重要人类病原体的调节机制和传染性。

项目成果

Quantitative analyses of interactions between SpoVG and RNA/DNA.

SpoVG 和 RNA/DNA 之间相互作用的定量分析。

• DOI: 10.1101/2023.02.06.527361
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Saylor,TimothyC;Savage,ChristinaR;Krusenstjerna,AndrewC;Jusufovic,Nerina;Zückert,WolframR;Brissette,CatherineA;Motaleb,Md;Schlax,PaulaJ;Stevenson,Brian
• 通讯作者: Stevenson,Brian

Gac Is a Transcriptional Repressor of the Lyme Disease Spirochete's OspC Virulence-Associated Surface Protein.

• DOI: 10.1128/jb.00440-22
• 发表时间: 2023-04-25
• 期刊: Journal of bacteriology
• 影响因子: 3.2