Immune Modulation During Acute Lyme Disease Infection as the Result of Aberrant Immunoglobulin Glycosylation

异常免疫球蛋白糖基化导致急性莱姆病感染期间的免疫调节

• 批准号: 10726417
• 负责人: Mary Ann Comunale
• 金额: $ 22.49万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726417
• 关键词: Acute; Acute Disease; American; Anti-Inflammatory Agents; Antibiotic Therapy; Antibodies; Antibody Therapy; Antigenic Variation; Antigens; B-Lymphocytes; Bacterial Infections; Binding; Biological Assay; Biological Markers; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi Group; Brain; COVID-19; Cells; Clinical; Complement; Complement 1q; Complement Activation; Complex; Contracts; Cytolysis; Data; Deposition; Development; Diagnostic tests; Disease; Early Diagnosis; Early treatment; Enzymes; Exoglycosidases; Fab Immunoglobulins; Fab domain; Fc Receptor; Fc domain; Functional disorder; Future; Galactose; Glycoengineering; Goals; HIV; Health; Heart; Human; Immune; Immune Evasion; Immune Targeting; Immune response; Immune signaling; Immunoglobulin Alterations; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunology procedure; Impairment; Incidence; Incubated; Infection; Inflammation; Inflammatory; Inflammatory Response; Intravenous; Intravenous Immunoglobulins; Joints; Label; Link; Lyme Disease; Lyme disease diagnosis; Lyme disease diagnostic; Masks; Measures; Mediating; Mucocutaneous Lymph Node Syndrome; Multiple Sclerosis; Nature; Order Spirochaetales; Organ; Patients; Pattern; Peptides; Polysaccharides; Population; Post-Translational Protein Processing; Reporting; Research; Rheumatoid Arthritis; Role; Sampling; Serum; Serum Proteins; Sialic Acids; Signal Transduction; Solid; Structure of germinal center of lymph node; Testing; Tuberculosis; Work; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; clinical diagnostics; diagnostic assay; glycosylated IgG; glycosylated IgM; glycosylation; immunoregulation; improved; in vitro Assay; lyme pathogenesis; neutravidin; novel; pathogen; potential biomarker; prevent; receptor; response; seroconversion; sugar

Abstract: Lyme disease (LD) leads to lifelong health problems if standard antibiotic therapy is not initiated during the first 2-3 weeks after infection. Diagnosis for LD currently relies on seroconversion and is unreliable during acute disease. Cases of suspected acute LD should be confirmed using clinical diagnostic assays. N- linked glycosylation is one of the most abundant post-translational modifications of serum proteins. While it is dynamic in nature, it is also highly consistent in a healthy state. N-linked glycosylation of serum immunoglobulins (Igs) are known to change in a disease specific manner and can direct the host immune response toward a pro- or an anti-inflammatory response. We previously observed that Ig N-glycans produced during acute LD contain specific alterations in the abidance of galactose and sialic acid. We hypothesize that these Ig alterations are antigen-specific, and that the glycosylation patterns present will negatively impact downstream immune responses. This hypothesis is based on our preliminary data, known LD B-cell perturbations, and reports of IgG N-glycans altering the immune response to COVID-19, tuberculosis, multiple sclerosis, and HIV. This proposal is novel and unique because it is the only study that examines the role of glycosylation during the human immune response to LD. This proposal is built on our preliminary work where we identified aberrant glycosylation on the total serum IgG and IgM in acute LD patients prior to seroconversion. In this proposal, we examine the glycosylation of Igs specific to LD antigens and determine if acute LD infection will alter B-cell responses to produce antigen specific Igs with the same unique glycosylation changes seen in our preliminary data. Additionally, we examine how the glycosylation pattern on antigen specific Igs effect the immune response to LD. In Aim 1, we isolate Igs specific to the LD antigen VlsE and establish the IgG and IgM N-glycan profiles. The result will determine if antigen specific Igs contain the same aberrant glycosylation found in the total Ig population of acute LD patients. In Aim 2, we quantify the impact of LD antigen-specific IgG glycosylation on the promotion of ADCC and complement deposition. The result will determine if there is a link between IgG glycosylation and the inability of the patients to clear the Borrelia burgdorferi spirochete that causes LD. In Aim 3, we quantify the impact of antigen-specific IgM glycosylation on the complement deposition rate. Complement deposition leads to rapid clearance of Lyme disease pathogens. Altered glycosylation of IgM could impair complement deposition and impede the ability of the human host to clear the infection. This work will establish a new mechanism of Borrelial immune evasion, characterize the host-response to LD pathogenesis in humans. Additionally, the results will potentiate the use of Ig N-glycans to serve as multiplexed biomarkers in a novel Lyme disease diagnostic assay and guide the glycoengineering of antibodies for use in intravenous therapy in hard-to-treat disseminated Lyme disease cases.

摘要：如果未开始标准抗生素治疗，莱姆病（LD）会导致终身健康问题 在感染后的前2-3周内。 LD的诊断目前依赖于血清转化，是不可靠的 在急性疾病期间。可疑的急性LD病例应使用临床诊断测定法确认。 n- 链接的糖基化是血清蛋白最丰富的翻译后修饰之一。虽然是 本质上，它在健康状态下也是高度一致的。血清免疫球蛋白的N连接糖基化 （IG）已知会以疾病特定的方式改变，并且可以将宿主免疫反应引导 或抗炎反应。我们先前观察到急性LD期间产生的Ig n-glycans包含 半乳糖和唾液酸的差异的特异性改变。我们假设这些IG改变是 抗原特异性，并且存在的糖基化模式将对下游免疫产生负面影响 回答。该假设基于我们的初步数据，已知的LD B细胞扰动和IgG的报告 N-聚糖改变了对Covid-19，结核病，多发性硬化和HIV的免疫反应。 该建议是新颖而独特的，因为它是唯一研究糖基化作用的研究 在人类对LD的免疫反应期间。该建议建立在我们确定的初步工作的基础上 在血清转化之前，急性LD患者的总血清IgG和IgM的异常糖基化。在这个 提案，我们检查了特定于LD抗原的Ig的糖基化，并确定急性LD感染是否会 改变B细胞反应以产生具有相同独特糖基化变化的抗原特异性Ig 初步数据。此外，我们研究了抗原特异性IG上的糖基化模式如何影响 对LD的免疫反应。 在AIM 1中，我们分离了特定于LD抗原VLSE的Igs，并建立IgG和IgM n-Glycan曲线。 结果将确定抗原特异性IG是否包含在总Ig中发现的相同异常糖基化 急性LD患者的种群。在AIM 2中，我们量化了LD抗原特异性IgG糖基化对该的影响 促进ADCC和补体沉积。结果将确定IgG之间是否存在链接 糖基化和患者无法清除导致LD的伯氏毛螺旋体。目标 3，我们量化了抗原特异性IgM糖基化对补体沉积速率的影响。补充 沉积导致莱姆病病原体的快速清除。 IgM的糖基化改变可能会损害 补体沉积并阻碍人类宿主清除感染的能力。 这项工作将建立一种新机制的疏疏hime逃避机制，是宿主反应的特征 在人类中发病。此外，结果将增强使用Ig n-glycans作为 新型莱姆病诊断测定中的多重生物标志物，并指导糖化工程 在难以治疗的传播莱姆病病例中用于静脉治疗的抗体。