Defining the antibody interface between Mycobacterium tuberculosis and host immunity

定义结核分枝杆菌与宿主免疫之间的抗体界面

• 批准号: 10493365
• 负责人: Lenette Lu
• 金额: $ 41.68万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493365
• 关键词: Address; Aerobic; Anaerobic Bacteria; Antibodies; Antibody Diversity; Antigens; Bacteria; Bacterial Infections; Binding; Biological Assay; CD4 Positive T Lymphocytes; Capillary Electrophoresis; Cell physiology; Cells; Cellular Immunity; Cessation of life; Chemicals; Chronic; Communicable Diseases; Data; Diagnostic; Disease; Disease Progression; Environment; Enzymes; Exhibits; Fab domain; Fc Receptor; Fc domain; Flow Cytometry; Goals; Growth; Human; Humoral Immunities; Hypoxia; Immune; Immune response; Immunity; Immunoglobulin G; Immunology; In Vitro; Individual; Infection; Inflammasome; Link; Lysosomes; Measures; Microbe; Modeling; Molecular; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Outcome; Pathway interactions; Pattern; Persons; Phagocytosis; Physiological; Population; Property; Publishing; Research; Risk; Role; Serodiagnoses; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tuberculosis; Vaccine Design; Vaccines; Viral Antibodies; Vision; Work; adaptive immune response; antibody-dependent cell cytotoxicity; antimicrobial; base; chronic infection; clinically significant; disease heterogeneity; glycosylation; in vitro Model; in vivo; in vivo Model; inhibitor; latent infection; macrophage; monocyte; mouse model; permissiveness; pressure; prevent; receptor; recruit; response; small hairpin RNA; tuberculosis immunity; vaccine development

Project Summary/Abstract: Tuberculosis (TB) kills 1.5 million people per year. Efforts to reduce this number have been hindered by the lack effective diagnostics and a protective vaccine underpinned by gaps in the understanding of the immune response in TB disease. While cellular immunity is important, the humoral immune response to infection by Mycobacterium tuberculosis (Mtb) is poorly understood. Antibodies, specifically IgG, are critical components of the adaptive immune response which have been indispensable in our understanding of infectious diseases and vaccine development. Antibodies function through the combination of recognizing antigens by the Fab domain and the recruitment of immune effector responses via the Fc domain. Variability in the Fc domain by isotype, subclass, and post translational glycosylation impact engagement with Fc receptors on immune cells that alter function in clinically significant manners. We have published that the antibody Fc domain diverges between individuals with latent infection who appear healthy and able to restrict bacteria compared to active TB disease which is permissive to Mtb replication. These distinctions are linked to differential Mtb burden in an in vitro primary human monocyte derived macrophage model of infection. How exactly antibodies might function in this context and its physiological relevance are questions that this proposal begins to address. The specific aims are 1: Determine how the Mtb antigenic repertoire impacts polyclonal IgG functions, 2: Identify the macrophage pathways by which the IgG Fc modulates Mtb survival, 3: Examine the in vivo effect of polyclonal IgG on chronic Mtb infection. The scientific objective of this proposal is to determine how polyclonal IgG contributes to restrictive and permissive host states for Mtb. The central hypothesis is that polyclonal IgG from individuals with active TB disease induces a host state permissive to bacterial growth. The overall goal is to understand fundamental mechanisms of humoral immunity in TB through antibodies to inform diagnostic, therapeutic and vaccine design.

项目摘要/摘要： 结核病 (TB) 每年夺去 150 万人的生命。减少这一数字的努力因缺乏 以免疫反应理解差距为基础的有效诊断和保护性疫苗 在结核病中。虽然细胞免疫很重要，但对分枝杆菌感染的体液免疫反应 人们对结核病（Mtb）知之甚少。抗体，特别是 IgG，是适应性的重要组成部分 免疫反应对于我们了解传染病和疫苗来说是不可或缺的 发展。抗体通过 Fab 结构域和识别抗原的结合发挥作用 通过 Fc 结构域招募免疫效应子反应。 Fc 结构域按同种型、亚类的变异性， 翻译后糖基化影响免疫细胞上 Fc 受体的结合，从而改变免疫细胞的功能 具有临床意义的方式。我们已经发表了抗体 Fc 结构域在个体之间存在差异 与活动性结核病相比，潜伏感染者看起来很健康并且能够限制细菌。 允许 Mtb 复制。这些区别与体外原代人类的 Mtb 负荷差异有关 单核细胞衍生的巨噬细胞感染模型。抗体在这种情况下究竟如何发挥作用及其 生理相关性是该提案开始解决的问题。具体目标是1：确定 Mtb 抗原库如何影响多克隆 IgG 功能，2：确定巨噬细胞通路 IgG Fc 调节 Mtb 存活，3：检查多克隆 IgG 对慢性 Mtb 感染的体内作用。这 该提案的科学目标是确定多克隆 IgG 如何有助于限制性和许可性 Mtb 的东道国。中心假设是来自活动性结核病个体的多克隆 IgG 会诱导 允许细菌生长的宿主状态。总体目标是了解基本机制 通过抗体对结核病进行体液免疫，为诊断、治疗和疫苗设计提供信息。