Cellular processing and role of a surface antigen in borrelial pathogenesis

表面抗原在疏螺旋体发病机制中的细胞加工和作用

• 批准号: 8430438
• 负责人: Xiuli Yang
• 金额: $ 6.84万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430438
• 关键词: Amino Acids; Antigens; Arthritis; Arthropods; Biological; Biology; Borrelia; Borrelia burgdorferi; CXCL1 gene; CXCL5 gene; Cell physiology; Cells; Computer Simulation; Cytokine Receptors; Data; Databases; Dermis; Development; Disease; Event; Goals; Heart; Human; IL8RB gene; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Ixodes; Joints; Kinetics; Length; Light; Lipoproteins; Lyme Arthritis; Lyme Disease; Mammals; Measures; Membrane Proteins; Microbe; Molecular; Molecular Weight; Mus; N-terminal; Nature; Nervous system structure; Neutrophil Infiltration; Order Spirochaetales; Organ; Outcome; Pathogenesis; Peptide Signal Sequences; Play; Preventive; Process; Production; Property; Protein Region; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Role; SCID Mice; Surface; Surface Antigens; Tandem Repeat Sequences; Therapeutic; Ticks; Tissues; Virulence; chemokine; chemokine receptor; cytokine; enzootic; feeding; in vivo; mutant; novel; pathogen; polypeptide; public health relevance; receptor

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.

描述（由申请人提供）：莱姆病是一种流行的节肢动物传播的疾病，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和哺乳动物的复杂的地方性动物循环而生存。在进食过程中，受感染的蜱可以将伯氏疏螺旋体传播到宿主真皮，螺旋体从那里传播到许多内脏器官，包括关节、心脏和神经系统，引起严重的炎症性疾病，统称为莱姆病或莱姆疏螺旋体病。某些炎症细胞的严重浸润是莱姆疏螺旋体病的一个主要特征，导致受感染器官的病理损伤。先前的研究表明，伯氏疏螺旋体具有有效的细胞因子刺激特性，并且螺旋体脂蛋白诱导促炎细胞因子的产生。我们最近涉及伯氏疏螺旋体基因产物的研究表明，抗原 Lmp1（注释为表面定位膜蛋白 1）是莱姆病病原体的毒力决定因素。尽管 Lmp1 在伯氏疏螺旋体毒力中发挥重要作用，但其在病原体生物学中的功能或其在螺旋体感染性中的贡献仍然未知。我们现在发现，天然全长 (128 kDa) Lmp1 蛋白的一部分在伯氏疏螺旋体中被加工成独特的低分子量多肽，并且与野生型螺旋体相比，lmp1 突变体的感染导致莱姆关节炎的严重程度减轻。我们当前提案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分子触发因素的潜在作用。这项研究将为螺旋体发病机制提供新的线索，也可能有助于开发针对莱姆病的新型预防措施。