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文摘

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