Host Spirochete Interactions in Lyme Disease

莱姆病中宿主螺旋体的相互作用

• 批准号: 7030116
• 负责人: JON T SKARE
• 金额: $ 36.38万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030116
• 关键词: Borrelia; Lyme disease; Spirochaetales; adhesin; binding proteins; decorin; fibronectins; genes; genetics; infection; mutant; protein binding; proteins; role

DESCRIPTION (provided by applicant): Infection with Borrelia burgdorferi leads to Lyme disease, which is the leading arthropod-borne infectious agent in the United States. Despite the prevalence of this disease, little is understood about the molecular pathogenesis of this infection. Inasmuch as bacterial adherence to host tissues is recognized as a critical component of the pathogenic process, we therefore propose to further characterize the B. burgdorferi decorin binding and BBK32 adhesins that bind to host decorin and fibronectin, respectively. Characterization of the adhesive properties of these borrelial microbial surface components that recognize extracellular matrix molecules will be conducted in concert with studies to address the infectivity of strains whose adhesin genes have been genetically inactivated either individually or in combination. To further characterize the borrelial lipoprotein adhesins and their respective mutants, we propose the following Specific Aims: (1) Define the role of the fibronectin binding BBK32 in B. burgdorferi pathogenesis; (2) Further characterize the role of the decorin binding proteins in B. burgdorferi pathogenesis; and (3) Evaluate the importance of selected lipoproteins in the molecular pathogenesis of B. burgdorferi infections. We have genetically inactivated the fibronectin binding adhesin in an infectious isolate of B. burgdorferi and have strong preliminary evidence that fibronectin binding participates in secondary colonization and/or protects the organism against clearance. This mutant represents the first genetic knockout in a lipoprotein encoding loci that has a known adhesive activity that targets a mammalian ligand. Similar analyses are planned for the genes encoding the decorin binding protein adhesins as well as genetic studies to evaluate a panel of novel lipoproteins for their importance for borrelial pathogenesis. Following initial characterization studies using in vitro correlates of infection, i.e., adhesion and invasion, we will then determine the molecular mechanism(s) these adhesins use to colonize, disseminate, and/or persist within the infected mammalian host(s).

描述（由申请人提供）：带有伯氏伯氏菌的感染导致莱姆病，莱姆病是美国领先的节肢动物传染剂。尽管这种疾病的流行率很少，但关于这种感染的分子发病机理几乎没有理解。因此，由于细菌对宿主组织的依从性被认为是致病过程的关键组成部分，因此我们建议进一步表征分别与宿主Decorin和fibronectin结合的B. burgdorferi Decorin结合和BBK32粘附素。这些骨质微生物表面成分的粘附特性的表征将与研究一起进行研究，以解决其粘附素基因在遗传上单独或组合被遗传失活的菌株的感染性。为了进一步表征丘脑脂蛋白粘附素及其各自的突变体，我们提出了以下特定目的：（1）定义纤连蛋白结合BBK32在B. burgdorferi发病机理中的作用； （2）进一步表征了装饰蛋白结合蛋白在B. burgdorferi发病机理中的作用； （3）评估选定的脂蛋白在B. burgdorferi感染的分子发病机理中的重要性。我们在遗传上使纤连蛋白结合蛋白在爆发芽孢杆菌的传染性分离株中灭活，并具有强烈​​的初步证据，表明纤连蛋白结合参与二次定植和/或保护生物体免受清除。该突变体代表了脂蛋白编码基因座的第一个遗传基因敲除，该基因座具有靶向哺乳动物配体的已知粘合剂活性。计划针对编码装饰蛋白结合蛋白粘附素的基因以及遗传研究，以评估新型脂蛋白小组对骨质发病的重要性。在最初使用体外感染相关性（即粘附和侵袭）的研究之后，我们将确定这些粘附素用于在感染的哺乳动物宿主内殖民，传播和/或持续存在的分子机制。