Host Spirochete Interactions in Lyme Disease

描述（由申请人提供）：感染伯氏疏螺旋体导致莱姆病，这是美国主要的节肢动物传播的传染病。尽管这种疾病很普遍，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分别与宿主decorin和纤维连接蛋白结合的伯氏疏螺旋体decorin结合和BBK32粘附素。这些识别细胞外基质分子的borrelial微生物表面组分的粘附特性的表征将与解决粘附素基因被单独或联合灭活的菌株的传染性的研究一起进行。为了进一步表征疏螺旋体脂蛋白粘附素及其突变体，我们提出以下具体目标：(1)明确纤维连接蛋白结合BBK32在伯氏疏螺旋体发病机制中的作用；(2)进一步表征了decorin结合蛋白在伯氏疏螺旋体发病机制中的作用；(3)评价选定脂蛋白在伯氏疏螺旋体感染分子发病机制中的重要性。我们通过基因灭活了伯氏疏螺旋体传染性分离株中的纤维连接蛋白结合粘附素，并有强有力的初步证据表明纤维连接蛋白结合参与了二次定植和/或保护生物体免受清除。该突变体是第一个基因敲除的脂蛋白编码位点，具有已知的粘附活性，针对哺乳动物配体。类似的分析计划用于编码decorin结合蛋白粘附素的基因，以及遗传学研究，以评估一组新型脂蛋白在螺旋体发病机制中的重要性。在使用体外感染相关因素（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植、传播和/或持续存在的分子机制。

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).