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Molecular Genetic Basis of the Infectious Cycle of Borrelia burgdorferi

伯氏疏螺旋体感染周期的分子遗传学基础

基本信息

批准号：
10927786
负责人：
PATRICIA A ROSA
金额：
$ 56.99万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927786
关键词：
Address Arthropod Vectors Bacteria Bacteria sigma factor KatF protein Bacteriophages Borrelia Borrelia burgdorferi Cellular Structures Chromosomes Complement Cues DNA Data Diagnosis Elements Engineering Environment Europe Fostering Genes Genetic Genome Genomic Segment Genomics Goals Individual Infection Investigation Ixodidae Link Location Lyme Disease Maintenance Mammals Mediating Metabolism Molecular Biology Molecular Genetics Mus Nature Order Spirochaetales Organism Pathogenesis Phenotype Phylogenetic Analysis Plasmids Play Principal Investigator Process Production Prophages Proteins Reporting Research Design Rodent Role Sigma Factor Signal Induction Signal Transduction Site Spirochaetales Infections Structure System Techniques Testing Tick-Borne Diseases Ticks United States Variant Virulence Work Zoonoses enzootic experimental study genetic analysis genetic approach genome-wide in vivo insight interest metabolomics mutant pathogen pathogenic bacteria prevent protein profiling response tick feeding tool transcriptomics transmission process vector tick vector-borne pathogen

项目摘要

Lyme disease is the most common tick-borne illness in the United States and Europe. It is caused by Borrelia burgdorferi, a bacterial pathogen that is maintained in nature in a zoonotic cycle between various species of small mammals and an ixodid tick vector. A hallmark of the Lyme disease spirochete is its unusual, segmented genome, comprising a linear chromosome and approximately 20 linear and circular plasmids. An increasing body of data demonstrates that plasmid-encoded functions are critical for successful adaptation of B. burgdorferi to the different environments that the spirochete encounters during its natural infectious cycle. We have developed genetic tools to investigate basic aspects of the unusual genomic organization, cellular structure and metabolism of B. burgdorferi. We have extended this investigation to an in vivo setting with an experimental system that closely mimics the natural arthropod vector/rodent host infectious cycle. Through an understanding of the basic molecular biology of the organism, we hope to gain insight into the infectious strategy utilized by this significant vector-borne pathogen and thereby facilitate efforts to prevent, diagnose and treat Lyme disease. The alternative sigma factor RpoS plays a central role in a critical adaptive response of the Lyme disease spirochete that is induced during tick feeding and prepares the spirochete for infection of the vertebrate host. Previous work from our lab identified the plasmid-encoded BBD18 protein as a negative regulator of RpoS, but inactivation of the bbd18 gene in wild-type spirochetes was never achieved. We utilized a conditional bbd18 mutant, genome-wide transcriptomic, metabolomic, and protein profiling, and the first engineered displacement of all cp32 prophage plasmids, to investigate the lethal phenotype that accompanies BBD18 depletion and unmodulated production of RpoS in infectious B. burgdorferi. Additionally, we conducted in vivo studies to identify the precise stage and location during the mouse-tick infectious cycle at which spirochetes require BBD18 for survival. As a result of these experiments, we provide the first report of a link between transducing phage and the RpoS-dependent adaptive response that Lyme disease spirochete undergo during tick feeding. We infer that the multipartite structure of the Borrelia genome facilitates phage-mediated genetic exchange and reassortment, and thereby fosters the level of diversity that is required for spirochete maintenance in the natural enzootic cycle. NOTE: The Principal Investigator retired in April 2023 and this project will be terminated/inactivated.

莱姆病是美国和欧洲最常见的蜱传疾病。它是由伯氏疏螺旋体引起的，伯氏疏螺旋体是一种细菌病原体，在自然界中存在于各种小型哺乳动物和蜱虫媒介之间的人畜共患循环中。莱姆病螺旋体的一个特征是其不寻常的分段基因组，包括一条线性染色体和大约20个线性和圆形质粒。越来越多的数据表明，质粒编码功能对于伯氏疏螺旋体在其自然感染周期中成功适应不同环境至关重要。我们已经开发了遗传工具来研究伯氏疏螺旋体不寻常的基因组组织，细胞结构和代谢的基本方面。我们已经将这项研究扩展到体内环境，使用实验系统密切模仿自然节肢动物媒介/啮齿动物宿主感染周期。通过对有机体基本分子生物学的了解，我们希望能够深入了解这种重要的媒介传播病原体所采用的感染策略，从而促进莱姆病的预防、诊断和治疗。