Humoral responses to Lyme Borreliosis: A mouse model

对莱姆疏螺旋体病的体液反应：小鼠模型

• 批准号: 7558313
• 负责人: STEPHEN WILLIAM BARTHOLD
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558313
• 关键词: A Mouse; Affinity; Antibodies; Antibody Formation; Antigen-Presenting Cells; Arthritis; Arthropods; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Binding Proteins; Biological Assay; Biological Response Modifiers; Bite; Borrelia; Borrelia Infections; Borrelia burgdorferi; CD4 Positive T Lymphocytes; Carditis; Chronic; Chronic Disease; Classification; Data; Defect; Development; Disease; Emerging Communicable Diseases; Europe; Failure; Fc Receptor; Feedback; Flow Cytometry; Heart; Heart failure; Helper-Inducer T-Lymphocyte; Immune response; Immune system; Immunity; Immunocompetent; Immunoglobulin G; Immunoglobulin M; Infection; Infectious Diseases Research; Joints; Lead; Life; Longevity; Lyme Disease; Lymphoid Tissue; Mediating; Modeling; Mus; Myocardium; Myopathy; NIH Program Announcements; Nature; Order Spirochaetales; Organ; Patients; Plasma Cells; Process; Prophylactic treatment; Recurrence; Regulation; Reporting; Resolution; Role; Shapes; Signal Transduction; Structure of germinal center of lymph node; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Ticks; Time; Tissues; Vaccines; base; biodefense; design; disabling disease; lymph nodes; mouse model; prophylactic; prototype; public health relevance; response

DESCRIPTION (provided by applicant): This proposal, which is responsive to the NIH Program Announcement on Non-Biodefense Emerging Infectious Diseases Research Opportunities, is concerned with Lyme borreliosis. This disease is caused by B. burgdorferi (Bb) and is the most commonly reported arthropod-borne illness in the US and Europe with the number of reported infections raising each year. The spirochetes cause persistent infections and chronic disease with bouts of arthritis and carditis in untreated patients. Our long-term objective is to delineate the mechanisms with which Bb evades effective immunity during persistent infection of fully immunocompetent hosts. Previous studies have identified antibodies as a main immune mediator of disease resolution (but not clearance of the spirochete) and passive protection. While antibodies in early infection are strongly functional with respect to disease-resolution and passive protective capacity, the protective capacity wanes as disease progresses. The objective of this proposal is to assess the mechanisms underlying the regulation of the Bb- specific humoral response, to ascertain whether strengthening of humoral responses could be exploited for therapeutic or prophylactic use. Based upon preliminary findings, we aim to test the hypothesis that Bb- specific B cells provide antibody responses by short-lived plasma cells at the expense of higher affinity B cells and long-lived plasma cells due to a lack of functional CD4 helper T cell activation. A murine model of Borrelia infection will be used to conduct three Specific Aims. Specific Aim #1 will determine the extent to which the early-induced specific IgM and/or IgG responses actively inhibit protective immunity using genetically altered mice unable to secrete certain Ig isotypes. Specific Aim #2 will test whether Bb drives lymph node B cell responses away from germinal center responses. This could result in the lack of affinity maturation and longevity and could cause a loss of functionality over time, as observed in Lyme Borrelioses. Assays will include multicolor flow cytometry to determine the nature and quality of the induced response. Furthermore, the responding B cell subsets will be identified and their regulation by CD4 T cells will be assessed. Also, the extent to which a lack of affinity maturation and development of long-lived plasma cells underlies the functional defect in the Bb-specific antibody responses will be determined by studying antibodies to decarin-binding protein as a prototype response. Specific Aim #3 will determine whether the lack of long- term functional B cell response induction to Borrelia is due to active inhibition and/or a failure of functional CD4 helper T cell response induction or whether an intrinsic defect in the ability of B cells to respond to T cell help underlies the lack of germinal center responses seen in Lyme Borreliosis. Together these studies will elucidate mechanisms that lead to the failure of the vigorous but ultimately deficient B cell response to facilitate clearance from Borrelia infection. PUBLIC HEALTH RELEVANCE: Lyme Disease is a chronic disabling disease resulting from a tick-bite. The tick transfers a bacterium, Borrelia burgdorferi, to the patient, which can persist in various organs, including the joints and heart, where it can cause disabling disease such as chronic arthritis and heart muscle disease. The body develops an immune response that can initially fend off disease but cannot clear the infection. Thus, if infections are not treated continuing disease is common. This proposal aims to determine why the immune response that is sufficient to help to reduce disease ultimately fails to clear the infection. Such information is necessary to develop vaccines and treatments for this increasingly prevalent disease.

描述（由申请人提供）：本提案是对NIH非生物防御新发传染病研究机会项目公告的响应，涉及莱姆病。这种疾病是由伯氏疏螺旋体（Bb）引起的，是美国和欧洲最常见的节肢动物传播疾病，报告的感染数量每年都在增加。螺旋体在未经治疗的患者中引起持续性感染和慢性疾病，包括关节炎和心脏病。我们的长期目标是描述Bb在完全免疫能力宿主持续感染期间逃避有效免疫的机制。先前的研究已经确定抗体是疾病解决（但不是清除螺旋体）和被动保护的主要免疫介质。虽然早期感染中的抗体在疾病消退和被动保护能力方面具有很强的功能，但随着疾病的进展，这种保护能力会减弱。本提案的目的是评估Bb特异性体液反应的调节机制，以确定是否可以用于治疗或预防使用强化体液反应。基于初步发现，我们的目标是验证这样一种假设，即由于缺乏功能性CD4辅助T细胞激活，Bb特异性B细胞通过短寿命浆细胞提供抗体反应，而牺牲了高亲和力B细胞和长寿命浆细胞。伯氏疏螺旋体感染的小鼠模型将用于进行三个特定目的。特异性目标#1将确定早期诱导的特异性IgM和/或IgG反应积极抑制保护性免疫的程度，使用无法分泌某些Ig同种型的转基因小鼠。特异性目标2将测试Bb是否驱动淋巴结B细胞反应远离生发中心反应。这可能导致缺乏亲和力成熟和寿命，并可能随着时间的推移导致功能丧失，正如莱姆病所观察到的那样。检测将包括多色流式细胞术，以确定诱导反应的性质和质量。此外，应答的B细胞亚群将被识别，CD4 T细胞对它们的调节将被评估。此外，在多大程度上缺乏亲和力成熟和长寿命浆细胞的发展是bb特异性抗体反应功能缺陷的基础，将通过研究decarin结合蛋白的抗体作为原型反应来确定。特异性目标#3将确定缺乏对疏螺旋体的长期功能性B细胞反应诱导是由于活性抑制和/或功能性CD4辅助性T细胞反应诱导的失败，还是B细胞对T细胞反应能力的内在缺陷有助于在莱姆病中缺乏生发中心反应。总之，这些研究将阐明导致强烈但最终缺乏的B细胞反应失败的机制，以促进对伯氏疏螺旋体感染的清除。