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）：感染伯氏疏螺旋体可导致莱姆病，莱姆病是美国主要的节肢动物传播的传染病。尽管这种疾病的流行，很少有人了解这种感染的分子发病机制。由于细菌对宿主组织的粘附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B。分别与宿主核心蛋白聚糖和纤连蛋白结合的burgdorferi核心蛋白聚糖结合素和BBK 32粘附素。这些疏螺旋体微生物表面成分识别细胞外基质分子的粘附特性的表征将与研究协同进行，以解决其粘附素基因已单独或组合遗传失活的菌株的感染性。为了进一步研究疏螺旋体脂蛋白粘附素及其突变体的特性，我们提出了以下具体目的：（1）确定纤维连接蛋白结合BBK 32在B中的作用。（2）进一步研究核心蛋白聚糖结合蛋白在B中的作用。评估所选脂蛋白在B分子发病机制中的重要性。伯氏菌感染我们已经在B的感染性分离株中遗传灭活了纤维连接蛋白结合粘附素。Burgdorferi，并且有强有力的初步证据表明纤连蛋白结合参与继发性定殖和/或保护生物体免于清除。该突变体代表了具有已知的靶向哺乳动物配体的粘附活性的脂蛋白编码基因座中的第一个遗传敲除。计划对编码核心蛋白聚糖结合蛋白粘附素的基因进行类似的分析，并进行遗传研究，以评估一组新型脂蛋白对疏螺旋体发病机制的重要性。在使用感染的体外相关性（即，粘附和侵袭，然后我们将确定这些粘附素用于在感染的哺乳动物宿主内定殖、散布和/或持续的分子机制。