Cellular processing and role of a surface antigen in borrelial pathogenesis

描述（由申请人提供）：莱姆病是一种普遍的节肢动物传播疾病，由细菌病原体伯氏疏螺旋体感染引起。这种微生物在自然界中通过涉及硬蜱、蜱和哺乳动物的复杂的地方病循环而存活。在进食期间，受感染的蜱可传播B。莱姆病螺旋体可将莱姆病螺旋体感染至宿主真皮，并从真皮扩散至包括关节、心脏和神经系统在内的多个内脏器官，引起统称为莱姆病或莱姆病疏螺旋体病的严重炎症性疾病。某些炎性细胞的严重浸润是莱姆疏螺旋体病的主要特征，其导致受感染器官的病理损伤。以前的研究表明，B。Burgdorferi具有有效的促肾上腺素的特性，并且螺旋体脂蛋白诱导促炎细胞因子的产生。我们最近的研究涉及B。burgdorferi基因产物的分析表明，抗原Lmp1，注释为表面定位的膜蛋白1，是莱姆病病原体的毒力决定因子。虽然Lmp 1在B.其在病原体生物学中的功能或其在螺旋体感染性中的作用仍然未知。我们现在发现，天然全长（128 kDa）Lmp1蛋白的一部分在B中被加工成不同的低分子量多肽。与野生型螺旋体相比，lmp 1突变体感染导致较不严重的莱姆关节炎。我们目前的建议的目标是更好地了解天然Lmp1的加工机制，并研究Lmp1作为宿主炎症性疾病的分子触发器的潜在作用。这项研究将为螺旋体致病机制提供新的线索，也可能有助于开发新的莱姆病预防措施。

DESCRIPTION (provided by applicant): Lyme disease, a prevalent arthropod-borne disease, results from infection with the bacterial pathogen Borrelia burgdorferi. The microbe survives in nature through an intricate enzootic cycle involving Ixodes ticks and mammals. During feeding, infected ticks can transmit B. burgdorferi to the host dermis, from where the spirochete disseminates to a number of internal organs including the joints, heart and nervous system, causing severe inflammatory disorders collectively known as Lyme disease or Lyme borreliosis. Severe infiltration of certain inflammatory cells is a major feature of Lyme borreliosis that contributes to pathological damage in the infected organs. Previous studies have demonstrated that B. burgdorferi possesses potent cytokine-stimulating properties and that spirochete lipoproteins induce the production of pro-inflammatory cytokines. Our recent studies involving B. burgdorferi gene products showed that the antigen Lmp1, annotated as surface-located membrane protein 1, is a virulence determinant of the Lyme disease pathogen. Although Lmp1 plays important roles in B. burgdorferi virulence, its function in the pathogen biology or its contribution in spirochete infectivity remains unknown. We now discovered that a fraction of native full-length (128 kDa) Lmp1 protein is processed into distinct lower-molecular weight polypeptides in B. burgdorferi and that infection with lmp1 mutants result in less severe Lyme arthritis compared to wild type spirochetes. The goal of our current proposal is to better understand the processing mechanism of native Lmp1 and study the potential role of Lmp1 as a molecular trigger of host inflammatory disorders. This study will shed new light on the mechanism of spirochete pathogenesis and may also help the development of novel preventive measures against Lyme disease.