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

• 批准号: 8186098
• 负责人: Nikhat Parveen
• 金额: $ 30.36万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 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/8186098
• 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; Image; 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; lyme pathogenesis; microbial; mouse model; mutant; novel; pathogen; quorum sensing; research study; response; treatment strategy

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. PUBLIC HEALTH RELEVANCE: Glycosamioglycan-mediated adherence of Lyme spirochetes to various mammalian cells appears to be a critical initial step during infection and also plays an important contribution in tissue colonization. Bgp is a GAG-binding adhesin that also exhibits 5'-methylthioadenosine/S-adenosylhomocysteine (MTA/SAH) nucleosidase activity. We will evaluate importance of these two activities of Bgp for infection in the mouse model and determine if Bgp-DbpA and DbpB are the major GAG-binding proteins required for B. burgdorferi pathogenesis.

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到每年2万例。病原体伯氏疏螺旋体通常在面对强烈的免疫反应时持续存在，并可导致使人丧失能力的慢性疾病表现，如关节炎或神经疏螺旋体病。我的长期目标是描述建立细菌感染和莱姆病所必需的宿主-细菌相互作用。许多微生物病原体在各种组织中的定殖需要附着于细胞或细胞外基质（ECM）。糖胺聚糖（Glycosaminoglycans，GAG）是蛋白聚糖的碳水化合物单元，其是在哺乳动物细胞上普遍表达的ECM组分。我们广泛的研究表明，GAG结合是B的主要粘附机制。burgdorferi。事实上，我们已经证明了B。伯氏疏螺旋体产生几种GAG结合粘附素，包括（i）DbpA和DbpB，（ii）疏螺旋体GAG结合蛋白（Bgp），和（iii）BBK 32。与GAG结合粘附素的多样性一致，缺乏一个或两个记录的莱姆病螺旋体粘附素的突变体保留一定程度的感染性。B。在多种菌株背景下产生的burgdorferi dbpA-dbp B双缺失突变体，我们的B. BurgdorferiBGP突变体和BBK 32突变体在免疫活性小鼠中保持感染性。其中至少前三种表现出定殖缺陷。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，目前尚不清楚bgp突变体的定植缺陷是否与其GAG结合活性、核苷酶活性或两者相关。为了确定bgp突变体的定植缺陷是否与其GAG结合、其酶活性或两者相关，以及Bgp是否与其他GAG结合粘附素显示部分功能冗余，将追求以下目标。（一）.描述Bgp的GAG结合和MTA/SAH核苷酶活性。（二）、定义感染期间定殖所需的Bgp活性。（三）、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是一种多功能的表面蛋白，观察了它在小鼠感染过程中的组织定殖作用，并确定它是新型药物的靶点。本研究将从遗传学角度描述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-Dbp B产生中的缺陷是否是累加的或各自有助于B的组织特异性定殖。burgdorferi。这样的螺旋体GAG的相互作用，涉及Bgp，DbpA和DbpB，对莱姆病的发病机制和Bgp作为代谢酶的作用的理解，可以帮助设计更好的诊断测试和促进新的治疗策略的发展，特别是对莱姆病的后期阶段。 公共卫生相关性：糖胺聚糖介导的莱姆病螺旋体对各种哺乳动物细胞的粘附似乎是感染过程中的关键初始步骤，并且在组织定殖中也起着重要作用。Bgp是一种GAG结合粘附素，也具有5 '-甲硫腺苷/S-腺苷高半胱氨酸（MTA/SAH）核苷酶活性。我们将在小鼠模型中评价Bgp的这两种活性对感染的重要性，并确定Bgp-DbpA和Dbp B是否是B所需的主要GAG结合蛋白。burgdorferi发病机制