Characteristics and protective efficacy of human antibodies against M. tuberculosis

人类结核分枝杆菌抗体的特点和保护功效

• 批准号: 10721412
• 负责人: Jacqueline Michele Achkar
• 金额: $ 4.49万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721412
• 关键词: Active Immunization; Affinity; Alternative Therapies; Antibodies; Antibody Therapy; Antibody-mediated protection; BCG Vaccine; Bacille Calmette-Guerin vaccination; Bacteria; Belief; Binding; Cause of Death; Cell Wall; Cells; Cellular Immunity; Characteristics; Communicable Diseases; Complex; Conjugate Vaccines; Data; Development; Disease; Epitopes; Foundations; Goals; Heterogeneity; Human; Humoral Immunities; Immune; Immune response; Immunoglobulin G; Immunotherapy; In Vitro; Knowledge; Lighting; Location; Macrophage; Mediating; Monoclonal Antibodies; Mus; Mycobacterium tuberculosis; Natural Immunity; Oligosaccharides; Passive Immunization; Phagocytosis; Polysaccharides; Proteins; Public Health; Publishing; Respiratory Tract Infections; Role; Sampling; South African; Specificity; Surface; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Virulence Factors; arm; capsule; experimental study; extracellular; glycosylation; human monoclonal antibodies; immunogenic; improved; in vivo; insight; lipoarabinomannan; novel; pathogen; pathogenic microbe; polyclonal human antibody; prevent; protective efficacy; response; tool; translational study; tuberculosis immunity; vaccination strategy; vaccine development

Abstract Active tuberculosis (TB), a transmissible respiratory infection caused by uncontrolled Mycobacterium tuberculosis (Mtb) infection, is worldwide one of the top 10 causes of death. To control this major global public health problem alternative therapies and a more effective vaccine are urgently needed. The currently available Bacillus Calmette-Guerin (BCG) vaccine has been in use for almost a century but provides insufficient protection against TB. A major obstacle in the TB vaccine field is the limited understanding of the full breadth of the immune components involved in the protection against TB. Currently, TB vaccine development is focused on eliciting or boosting cell-mediated immunity, but increasing evidence suggests that antibodies also have a role in the protection against TB. To gain a better understanding of the epitopes involved in human protection and inducible by vaccination, detailed characterization and functional studies of human polyclonal and monoclonal Abs (mAbs) to potentially protective epitopes are required. Antibodies to capsular and other surface polysaccharides are protective against several microbial pathogens, including those with intracellular location. Using novel glycan arrays our published and preliminary data show that human Abs to Mtb surface glycans are highly heterogeneous in their binding specificity and differ in both their reactivity to oligosaccharide motifs and their functions between BCG vaccination and/or controlled (latent) versus uncontrolled (TB) Mtb infection. Our overarching hypotheses are: 1) Human Abs to AM are protective against Mtb, and 2) protection by these Abs arises from reactivity to specific OS motifs within AM. Our specific aims are: 1. To generate and characterize human polyclonal and mAbs to Mtb surface glycans; 2. To determine the effects of Mtb surface- specific human Abs on macrophage functions; and 3. To establish the protective efficacy of Mtb surface- specific human Abs in vivo. Our overarching goal is to identify key immunogenic Mtb glycotopes that render Ab-mediated protection in humans. The information gained could fill a critical gap in the current knowledge of TB immunity and inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.

抽象的 活性结核病（TB），这是由不受控制的分枝杆菌引起的可传播呼吸道感染 结核病（MTB）感染是全世界的十大死亡原因之一。控制这个主要的全球公众 迫切需要健康问题替代疗法和更有效的疫苗。当前可用 芽孢杆菌Calmette-Guerin（BCG）疫苗已经使用了近一个世纪，但提供了不足 防止结核病。结核病疫苗领域的主要障碍是对全部广度的有限理解 与结核病保护有关的免疫成分。目前，结核病疫苗开发集中 关于引发或增强细胞介导的免疫力，但越来越多的证据表明抗体也具有 在防止结核病保护中的作用。为了更好地了解人类保护所涉及的表位 并通过疫苗接种，人类多克隆和 需要单克隆ABS（mAb）至潜在的保护性表位。抗体和其他抗体 表面多糖可抵抗几种微生物病原体，包括细胞内的病原体 地点。使用新颖的聚糖阵列我们发表的初步数据表明，人类ABS到MTB表面 聚糖的结合特异性高度异质，并且对寡糖的反应性有所不同 BCG疫苗接种和/或受控（潜在）与不受控制的（TB）MTB之间的图案及其功能 感染。我们的总体假设是：1）人类腹肌对MTB具有保护作用，2） 通过这些ABS，AM内的反应性对特定的OS基序产生。我们的具体目的是：1。生成和 将人类多克隆和mAb表征为MTB表面聚糖； 2。确定MTB表面的影响 特定的人类ABS在巨噬细胞功能上；和3。建立MTB表面的保护疗效 体内特定的人类腹肌。我们的总体目标是识别呈现呈现的关键免疫原性MTB糖基质 AB介导的人类保护。获得的信息可能会填补当前知识的关键差距 结核病的免疫力并为开发疫苗和基于AB的免疫疗法的新策略提供信息 TB。