Host Spirochete Interactions in Lyme Disease

莱姆病中宿主螺旋体的相互作用

基本信息

批准号：
7613339
负责人：
JON T SKARE
金额：
$ 34.65万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
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/7613339
关键词：
Address Adherence Adhesions Adhesives Alleles Animal Model Arthropods Attenuated Bacteria Bacterial Adhesins Binding Binding Proteins Biochemical Biological Biological Assay Borrelia Borrelia burgdorferi Case Study Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Complement Coupled Data Disease Experimental Models Extracellular Matrix Fibronectins Genes Genetic Immunity In Vitro Infection Infectious Agent Integrins Kinetics Knock-out Knowledge Ligands Lipoprotein (a)Lipoproteins Little&apos s Disease Lyme Disease Molecular Mus Mutagenesis Order Spirochaetales Organism Pathogenesis Positioning Attribute Prevalence Process Property Proteins Proteoglycan Research Personnel Role Site Specificity Staging Structure Surface System Tissues United States Virulence Work base decorin decorin binding protein B in vivo insight lyme pathogenesis microbial mutant novel pathogen programs success tissue tropism

项目摘要

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）：伯氏疏螺旋体感染会导致莱姆病，莱姆病是美国主要的节肢动物传播的传染原。尽管这种疾病很流行，但人们对这种感染的分子发病机制知之甚少。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伯氏疏螺旋体核心蛋白聚糖结合和分别与宿主核心蛋白聚糖和纤连蛋白结合的 BBK32 粘附素。这些识别细胞外基质分子的疏螺旋体微生物表面成分的粘附特性的表征将与研究相结合进行，以解决粘附素基因已被单独或组合遗传失活的菌株的感染性。为了进一步表征疏螺旋体脂蛋白粘附素及其各自的突变体，我们提出以下具体目标：（1）明确纤连蛋白结合BBK32在伯氏疏螺旋体发病机制中的作用； (2)进一步表征核心蛋白聚糖结合蛋白在伯氏疏螺旋体发病机制中的作用； (3) 评估选定的脂蛋白在伯氏疏螺旋体感染的分子发病机制中的重要性。我们已经在伯氏疏螺旋体感染性分离株中对纤连蛋白结合粘附素进行了基因灭活，并且有强有力的初步证据表明纤连蛋白结合参与了二次定植和/或保护生物体免遭清除。该突变体代表了脂蛋白编码位点中的第一个基因敲除，该位点具有已知的针对哺乳动物配体的粘附活性。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，并进行遗传学研究，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）进行初步表征研究之后，我们将确定这些粘附素用于在受感染的哺乳动物宿主内定殖、传播和/或持续存在的分子机制。