DbpA/B proteins of Borrelia burgdorferi & Lyme arthritis

描述(申请人提供)：莱姆病是一种独特的临床系统，用于研究慢性炎症性疾病的细胞和分子机制。这种疾病是由伯氏疏螺旋体引起的，是美国最流行的节肢动物传播疾病。这是一种影响皮肤、肌肉、关节、心脏和神经系统的多系统疾病。如果不治疗，慢性症状经常被观察到，莱姆关节炎是北美最常见的症状。我的长期目标是确定与宿主细胞附着和各种组织定植有关的伯氏杆菌毒力因子，并表征它们在慢性莱姆病发病机制、诊断和预防中的作用。糖胺多聚糖(GAG)广泛表达于所有有核细胞的表面，被各种莱姆氏螺旋体识别，多种细菌分子参与这种黏附。伯氏假单胞菌的核心蛋白结合素结合脂蛋白DbpA和DbpB除了蛋白多糖核心蛋白外，还与肝素和硫酸皮肤素有亲和力。我的假设是，DbpA和DbpB有助于Burgdorferi与宿主细胞上存在的Gag和Decorin结合的各种组织的定植，并在皮肤和关节引发炎症反应，导致红斑、迁徙和莱姆关节炎。这项研究要解决的主要问题是：(1)DbpA和DbpB是否参与了GAGS介导的伯氏杆菌与宿主细胞的附着和易感小鼠关节的炎症反应？(2)DBpA和DBpB基因的缺失是否影响Burgdorferi与宿主细胞的附着？(3)DbpA和DbpB脂蛋白是引发莱姆关节炎的Burgdorferi脂蛋白的基本毒力因子吗？症状：莱姆关节炎表现出几种与类风湿性关节炎相似的症状。然而，与类风湿性关节炎不同，莱姆病的病因是已知的，因此，分析这种破坏性关节炎的分子机制是可行的。此外，B.Burgdorfer/感染的小鼠表现出与人类莱姆病相似的症状，因此，小鼠模型为分析莱姆病的发病机制提供了一个理想的系统。这项研究将表征两种螺旋体脂蛋白粘附素在莱姆关节炎小鼠模型中的作用。

DESCRIPTION (provided by applicant): Lyme disease presents a unique clinical system to study cellular and molecular mecahnisms responsible for chronic inflammatory diseases. The disease, caused by the spirochete Borrelia burgdorfen, is the most prevalent arthropod borne disease in the United States. It is a multisystemic illness that affects skin, muscles, joints, heart and nervous system. If left untreated, chronic manifestations are frequenctly observed and Lyme arthritis is the most common symptom in North America. My Iong term qoal is to identify the virulence factors of B. burgdorferi involved in attachment to host cells and in colonization of various tissues, and characterize their role in the pathogenesis, diagnosis and prevention of chronic Lyme disease. Glycosaminoglycans (GAGs), ubiquitously expressed on the surface of all nucleated cells, are recognized by various Lyme spirochetes and several bacterial molecules are involved in this adherence. Decorin binding lipoproteins DbpA and DbpB of B. burgdorferi show affinity for heparin and dermatan sulfate GAGs in addition to the proteoglycan decorin. My hypothesis is that DbpA and DbpB contribute to the colonization of various tissues by B. burgdorferi binding to GAGs and decorin present on the host cells and trigger an inflammatory response in skin and joints causing erythema migrans and Lyme arthritis. The major question to be addressed in this study are: (1) Do DbpA and DbpB contribute to the GAGsmediated attachment of B. burgdorferi to host cells and to the inflammatory response in the joints of susceptible mice? (2) Does deletion of dbpA and dbpB genes affect attachment of B. burgdorferi to the host cells? (3) Are DbpA and DbpB lipoproteins essential virulence factors of B. burgdorferi that trigger Lyme arthritis? Si,qniflcance: Lyme arthritis exhibits several symptoms similar to those of rheumatoid arthritis. However, unlike rheumatoid arthritis, the causative agent is known in Lyme disease and hence, it is feasible to analyze the molecular mechanisms involved in this form of destructive arthritis. In addition, B. burgdorfer/ infected mouse exhibits symptoms similar to those of human Lyme disease, and hence, murine model provides an ideal system to analyze the mechanisms of Lyme borreliosis. This study will characterize the role of two spirochete lipoprotein adhesins in Lyme arthritis in the murine model.