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: 10365049
• 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/10365049
• 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; 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/antagonist; 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）每年造成150万人丧生。减少这一数字的努力受到缺乏的阻碍 在理解免疫反应时，有效的诊断和由差距支撑的保护性疫苗 在结核病疾病中。虽然细胞免疫很重要，但分枝杆菌对感染的体液免疫反应 结核病（MTB）知之甚少。抗体，特别是IgG，是自适应的关键组成部分 在我们对传染病和疫苗的理解中，免疫反应是必不可少的 发展。抗体通过识别Fab结构域识别抗原的组合起作用 通过FC域募集免疫效应子响应。通过同种型，子类，FC域的可变性， 并在翻译糖基化后影响与FC受体的参与对改变功能的免疫细胞 临床上重要的举止。我们已经发表了抗体FC域在患有 与活动性结核病相比，潜在感染看起来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中的差异MTB负担有关 单核细胞衍生的感染模型。在这种情况下及其ITS抗体可能确切起作用 生理相关性是该提案开始解决的问题。具体目的是1：确定 MTB抗原曲目如何影响多克隆IgG功能，2：确定巨噬细胞途径 IgG FC调节MTB存活率，3：检查多克隆IgG对慢性MTB感染的体内影响。这 该提案的科学目标是确定多克隆IgG如何促进限制性和允许性 MTB的主机状态。中心假设是来自活性结核病患者的多克隆IgG诱导 宿主状态允许细菌生长。总体目标是了解 通过抗体在结核病中的体液免疫，以告知诊断，治疗和疫苗设计。