Molecular trigger of Lyme arthritis

莱姆关节炎的分子触发因素

• 批准号: 7303635
• 负责人: UTPAL PAL
• 金额: $ 7.5万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7303635
• 关键词: Affect; Affinity; Antibodies; Antigens; Arthritis; Arthropod Vectors; Arthropods; Borrelia burgdorferi; Complement; Complication; Data; Disease; Disease regression; Gene Expression; Generations; Genes; Genetic; Goals; Human; Immune response; Inflammation; Inflammatory; Inflammatory Response; Joints; Lead; Life Cycle Stages; Location; Lyme Arthritis; Lyme Disease; Measures; Molecular; Mus; Numbers; Order Spirochaetales; Outcome; Pathogenesis; Patients; Phenotype; Play; Preventive; Proteins; Range; Reverse Transcriptase Polymerase Chain Reaction; Role; Severities; Spirochaetales Infections; System; Time; Tissues; United States; base; case finding; genetic manipulation; insight; microbial; mutant; pathogen

DESCRIPTION (provided by applicant): Murine Lyme arthritis results from Borrelia burgdorferi colonization of joints and the ensuing host response. In a mammalian host, B. burgdorferi persists in a wide range of tissues and we hypothesize that spirochetes induced selected genes - in precise host location and in time - and that these gene products are critical for the spirochete persistence and genesis of the disease, such as Lyme arthritis. Using microarray-based differential analysis of B. burgdorferi gene expression in murine tissues, and quantitative RT-PCR, we have now identified a spirochete gene, bmpA, which is preferentially upregulated in murine joints compared to other tissues. Interestingly, transfer of BmpA-specific antibodies into B. burgdorferi-infected mice selectively reduced spirochete numbers and inflammation in the joints. The goals of this proposal are, therefore, to generate B. burgdorferi lacking bmpA and further explore the role of this joint-induced protein in the pathogenesis of Lyme arthritis. We will assess if bmpA mutant B. burgdorferi will be infectious in mice but unable to effectively persist in joints. Also, we will determine if the bmpA mutant fails to induce arthritis and whether complementation of the mutant B. burgdorferi with the bmpA gene will restore the original phenotype. As BmpA is highly induced in infected joints, we will determine if this specific spirochete protein plays a greater role in triggering the host inflammatory response. We will measure alteration of selected host immunomodulatory factors in mice infected with wild type or bmpA mutants. These data will delineate the critical role of the differentially produced B. burgdorferi antigens in the spirochete infection of joints. Furthermore, our may lead to the new strategies for the treatment of Lyme arthritis.

描述（由申请人提供）： 鼠莱姆关节炎是由伯氏疏螺旋体在关节定植和随后的宿主反应引起的。在哺乳动物宿主中，伯氏疏螺旋体在广泛的组织中持续存在，我们假设螺旋体在精确的宿主位置和时间上诱导选定的基因，并且这些基因产物对于螺旋体的持续存在和疾病的发生至关重要，例如如莱姆关节炎。使用基于微阵列的小鼠组织中伯氏疏螺旋体基因表达的差异分析和定量 RT-PCR，我们现在已经鉴定出螺旋体基因 bmpA，与其他组织相比，该螺旋体基因在小鼠关节中优先上调。有趣的是，将 BmpA 特异性抗体转移到伯氏疏螺旋体感染的小鼠体内可以选择性地减少螺旋体数量和关节炎症。因此，该提案的目标是产生缺乏 bmpA 的伯氏疏螺旋体，并进一步探索这种关节诱导蛋白在莱姆关节炎发病机制中的作用。我们将评估 bmpA 突变体伯氏疏螺旋体是否在小鼠中具有感染性，但无法有效地在关节中持续存在。此外，我们将确定 bmpA 突变体是否不能诱导关节炎，以及突变体伯氏疏螺旋体与 bmpA 基因的互补是否会恢复原始表型。由于 BmpA 在受感染的关节中高度诱导，我们将确定这种特定的螺旋体蛋白是否在触发宿主炎症反应中发挥更大的作用。我们将测量感染野生型或 bmpA 突变体的小鼠中选定宿主免疫调节因子的变化。这些数据将描述差异产生的伯氏疏螺旋体抗原在关节螺旋体感染中的关键作用。此外，我们可能会带来治疗莱姆关节炎的新策略。