Borrelia burgdorferi-glycosaminoglycan interactions and Lyme disease pathogenesis

伯氏疏螺旋体-糖胺聚糖相互作用和莱姆病发病机制

基本信息

批准号：
8718996
负责人：
Nikhat Parveen
金额：
$ 35.78万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8718996
关键词：
Active Sites Address Adenosylhomocysteine nucleosidase Adherence Adhesives Affect Alleles Antibodies Arthritis Bacterial Adhesins Bacterial Infections Behavior Binding Binding Proteins Bioluminescence Borrelia Borrelia burgdorferi Carbohydrates Case Study Cell Line Cells Chronic Disease Complement Defect Dermatan Sulfate Development Diagnostic tests Disease Dose Drug Metabolic Detoxication Elements Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Exhibits Extracellular Matrix Glycosaminoglycans Goals Growth Heart Heparin Homologous Gene Immune response Immunocompetent In Vitro Infection Joints Knock-out Laboratories Lipoprotein Binding Lyme Arthritis Lyme Disease Lyme Neuroborreliosis Mammalian Cell Mediating Membrane Proteins Metabolic Metabolism Mus Musculoskeletal System Needles Nervous system structure Nucleoside Hydrolases Order Spirochaetales Pathogenesis Pharmaceutical Preparations Play Production Proteoglycan Recombinants Residual state Role Site Skin Staging System Tick-Borne Diseases Ticks Tissues Variant bactericide decorin decorin binding protein B design feeding genetic regulatory protein in vivo in vivo imaging lyme pathogenesis microbial mouse model mutant novel pathogen quorum sensing research study response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Lyme disease is the most prevalent tick-borne disease in the USA and affects the heart, joints, skin, musculoskeletal and nervous systems. Recently, the reported cases in the USA have increased to e20,000 per year. The causative agent, Borrelia burgdorferi, often persists in the face of a strong immune response and can result in incapacitating chronic disease manifestations, such as arthritis or neuroborreliosis. My long-term goal is to describe the host-bacterial interactions essential for establishment of the bacterial infection and consequently Lyme disease. Colonization of various tissues by many microbial pathogens requires attachment to cells or extracellular matrix (ECM). Glycosaminoglycans (GAGs) are carbohydrate units of proteoglycans, which are ubiquitously expressed ECM components on mammalian cells. Our extensive studies show that GAG-binding is a major adherence mechanism of B. burgdorferi. Indeed, we have shown that B. burgdorferi produces several GAG- binding adhesins, including, (i) DbpA and DbpB, (ii) Borrelia GAG-binding Protein (Bgp), and (iii) BBK32. Consistent with the multiplicity of GAG-binding adhesins, mutants lacking one or two documented adhesins of Lyme spirochetes retain some degree of infectivity. B. burgdorferi dbpA-dbpB double deletion mutants, generated in a variety of strain backgrounds, our B. burgdorferi bgp mutants, and bbk32 mutants remain infectious in immunocompetent mice. At least first three of these exhibit colonization defect. Bgp also exhibits 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase activity. However, it is not known if the colonization defect of the bgp mutant is related to its GAG-binding activity, its nucleosidase activity, or both. To determine if the defect in colonization by a bgp mutant is related to its GAG-binding, its enzymatic activity, or both, and whether Bgp displays partial functional redundancy with other GAG-binding adhesins, the following aims will be pursued. (1). Delineate the GAG-binding and MTA/SAH nucleosidase activities of Bgp. (2). Define the activity of Bgp required for colonization during infection. (3). Assess the functional redundancy of Bgp with other GAG-binding adhesins during colonization. Significance. We first recognized Bgp as a multifunctional surface protein, observed its role in tissue colonization during mouse infection, and determined it to be a target of novel drugs. This study will genetically delineate two activities of Bgp to assess if one or both activities are required during infection. We will also determine if defect in Bgp and DbpA-DbpB production is additive or each contribute to the tissue- specific colonization by B. burgdorferi. Such an understanding of the spirochete-GAG interactions involving Bgp, DbpA and DbpB, on Lyme pathogenesis and of the role of Bgp as a metabolic enzyme could help design better diagnostic tests and facilitate the development of novel treatment strategies, especially for the later stages of Lyme disease.

描述（由申请人提供）：莱姆病是美国最流行的蜱传疾病，影响心脏、关节、皮肤、肌肉骨骼和神经系统。最近，美国报告的病例已增加至每年 20,000 例。病原体伯氏疏螺旋体在强烈的免疫反应下通常会持续存在，并可能导致丧失能力的慢性疾病表现，例如关节炎或神经疏螺旋体病。我的长期目标是描述宿主与细菌之间的相互作用，这对于细菌感染以及莱姆病的形成至关重要。许多微生物病原体在各种组织中的定植需要附着在细胞或细胞外基质 (ECM) 上。糖胺聚糖 (GAG) 是蛋白聚糖的碳水化合物单位，是哺乳动物细胞上普遍表达的 ECM 成分。我们的广泛研究表明，GAG 结合是伯氏疏螺旋体的主要粘附机制。事实上，我们已经证明伯氏疏螺旋体产生几种 GAG 结合粘附素，包括 (i) DbpA 和 DbpB、(ii) 伯氏疏螺旋体 GAG 结合蛋白 (Bgp) 和 (iii) BBK32。与 GAG 结合粘附素的多样性一致，缺乏一种或两种记录的莱姆螺旋体粘附素的突变体保留了一定程度的感染性。在各种菌株背景中产生的伯氏疏螺旋体 dbpA-dbpB 双缺失突变体、我们的伯氏疏螺旋体 bgp 突变体和 bbk32 突变体在免疫功能正常的小鼠中仍然具有感染性。其中至少前三个表现出定植缺陷。 Bgp 还表现出 5'-甲硫腺苷/S-腺苷高半胱氨酸核苷酶活性。然而，尚不清楚 bgp 突变体的定植缺陷是否与其 GAG 结合活性、核苷酶活性或两者有关。为了确定 bgp 突变体的定植缺陷是否与其 GAG 结合、酶活性或两者有关，以及 Bgp 是否与其他 GAG 结合粘附素表现出部分功能冗余，将追求以下目标。 (1).描绘 Bgp 的 GAG 结合和 MTA/SAH 核苷酶活性。（2）。定义感染期间定植所需的 Bgp 活性。（3）。评估 Bgp 与其他 GAG 结合粘附素在定植过程中的功能冗余。意义。我们首先认识到 Bgp 是一种多功能表面蛋白，观察了其在小鼠感染期间组织定植中的作用，并确定其作为新药物的靶点。这项研究将从基因角度描述 Bgp 的两种活性，以评估感染期间是否需要一种或两种活性。我们还将确定 Bgp 和 DbpA-DbpB 生产中的缺陷是否是累加性的，或者是否均有助于伯氏疏螺旋体的组织特异性定植。了解涉及 Bgp、DbpA 和 DbpB 的螺旋体-GAG 相互作用、莱姆病发病机制以及 Bgp 作为代谢酶的作用，有助于设计更好的诊断测试并促进新治疗策略的开发，特别是对于莱姆病的后期阶段。莱姆病。