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: 8291968
• 负责人: Nikhat Parveen
• 金额: $ 35.1万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291968
• 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.

描述（由申请人提供）：莱姆病是美国最普遍的壁虱传播疾病，影响心脏，关节，皮肤，肌肉骨骼和神经系统。最近，美国的案件每年增加到E20,000。病因剂，伯氏伯氏菌通常会在强烈的免疫反应中持续存在，并可能导致慢性疾病表现能力，例如关节炎或神经性疾病。我的长期目标是描述建立细菌感染和因此莱姆病至关重要的宿主 - 细菌相互作用。许多微生物病原体对各种组织的定殖需要附着在细胞或细胞外基质（ECM）上。糖胺聚糖（GAGS）是蛋白聚糖的碳水化合物单位，它们在哺乳动物细胞上无处不在表达的ECM成分。我们的广泛研究表明，插科打结合是B. burgdorferi的主要依从性机制。实际上，我们已经表明，B。burgdorferi产生了几种结合粘合剂，包括（i）DBPA和DBPB，（ii）Borrelia oflelia gag结合蛋白（BGP）和（iii）BBK32。与多种结合粘合剂的多样性一致，缺乏一个或两个有记录的莱姆螺旋体粘附的突变体保留了一定程度的感染性。 B. burgdorferi dbpa-dbpb双重缺失突变体，在多种应变背景，我们的B. burgdorferi bgp突变体和BBK32突变体在免疫能力小鼠中仍然具有感染性。至少这些表现出定植缺陷的前三个。 BGP还表现出5'-甲基硫代腺苷/s-腺苷安全性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，其核苷酶活性或两者有关。为了确定BGP突变体在定植中的缺陷是否与其堵嘴，酶促活性或两者都相关，以及BGP是否与其他GAG结合粘合剂一起显示部分功能冗余，以下目标将被追求。 （1）。描绘BGP的GAG结合和MTA/SAH核苷酶活性。 （2）。定义感染过程中定植所需的BGP活性。 （3）。在定殖过程中，用其他GAG结合蛋白评估BGP的功能冗余性。意义。我们首先将BGP识别为多功能表面蛋白，观察到其在小鼠感染过程中的作用，并确定其是新药的靶标。这项研究将遗传描述BGP的两种活动，以评估感染过程中是否需要一项或两种活动。我们还将确定BGP和DBPA-DBPB的缺陷是否是加性的，或者每种都会导致B. burgdorferi的组织特异性定植。对涉及BGP，DBPA和DBPB的螺旋体GAG相互作用的理解，对莱姆病发病机理以及BGP作为代谢酶的作用可以帮助设计更好的诊断测试，并促进新型治疗策略的发展，尤其是在莱姆病的后期。