DbpA/B proteins of Borrelia burgdorferi & Lyme arthritis

描述（由申请人提供）：莱姆病提供了一个独特的临床系统来研究慢性炎症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，是美国最常见的节肢动物传播疾病。它是一种多系统疾病，影响皮肤、肌肉、关节、心脏和神经系统。如果不及时治疗，经常会出现慢性症状，莱姆病是北美最常见的症状。我的长期目标是确定伯氏疏螺旋体附着于宿主细胞和在各种组织定植的毒力因子，并表征其在慢性莱姆病发病、诊断和预防中的作用。糖胺聚糖（GAGs）在所有有核细胞表面普遍表达，被各种莱姆病螺旋体识别，并且一些细菌分子参与了这种粘附。伯氏疏螺旋体的Decorin结合脂蛋白DbpA和DbpB除蛋白聚糖Decorin外，还对肝素和硫酸皮肤聚糖GAGs具有亲和力。我的假设是，DbpA和DbpB与宿主细胞上存在的gag和decorin结合，促进伯氏疏螺旋体在各种组织中的定植，并引发皮肤和关节的炎症反应，导致移行性红斑和莱姆病关节炎。本研究需要解决的主要问题是：(1)DbpA和DbpB是否参与了gags介导的伯氏疏螺旋体对宿主细胞的附着以及易感小鼠关节的炎症反应？(2) dbpA和dbpB基因的缺失是否会影响伯氏疏螺旋体对宿主细胞的附着？(3) DbpA和DbpB脂蛋白是诱发莱姆病的伯氏疏螺旋体必需毒力因子吗？特征：莱姆病表现出与类风湿关节炎相似的几种症状。然而，与类风湿关节炎不同的是，莱姆病的致病因子是已知的，因此分析这种破坏性关节炎的分子机制是可行的。此外，伯氏疏螺旋体感染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机制提供了理想的系统。本研究将在小鼠模型中表征两种螺旋体脂蛋白粘附素在莱姆病中的作用。

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.