Characterizing the humoral response to lipoarabinomannan in tuberculosis progression

描述结核病进展中对阿拉伯脂甘露聚糖的体液反应

• 批准号: 10548577
• 负责人: Leela Davies
• 金额: $ 19.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548577
• 关键词: Adolescent; Animal Model; Antibiotics; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Bar Codes; Binding; Bioinformatics; Biological Assay; Biological Markers; Biophysics; Cause of Death; Cell physiology; Clinical; Communicable Diseases; Complex; Data; Development; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dissection; Engineering; Ensure; Epitopes; Fc Receptor; Fortune; Foundations; Future; Glycobiology; Glycolipids; HIV; HIV Seronegativity; HIV Seropositivity; Hospitals; IgG1; Immune; Immunoglobulin G; Immunoglobulin M; Immunology; In Vitro; Individual; Infection Control; Institutes; International; Laboratories; Libraries; Mediating; Mediator of activation protein; Medicine; Mentors; Methodology; Microbiology; Monoclonal Antibodies; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; NK Cell Activation; Names; Oligosaccharides; Persons; Physicians; Polysaccharides; Population; Predictive Value; Prevalence; Property; Public Health Schools; Regimen; Research; Resolution; Risk; Role; Serology; South African; Specificity; Surface; System; T-Lymphocyte; Therapeutic; Time; Training; Tuberculosis; Vaccines; Vision; Whole Blood; Woman; Work; antimicrobial; clinically relevant; co-infection; cohort; design; high risk; in vivo; innovation; instructor; interdisciplinary approach; lipoarabinomannan; medical schools; mortality; mycobacterial; novel diagnostics; novel marker; novel strategies; novel therapeutic intervention; predicting response; predictive signature; prevent; receptor binding; response; responsible research conduct; sugar; translational research program

PROJECT SUMMARY/ABSTRACT Reducing progression to active TB disease in individuals infected with Mycobacterium tuberculosis (Mtb) is a key component of eradicating TB worldwide, yet it is hampered by poor predictive value of existing diagnostics, cumbersome antibiotic regimens, lack of understanding of immune mechanisms of control, and absence of an effective vaccine. A growing field of research implicates antigen-specific antibodies as critical biomarkers and mediators of control of Mtb infection, implicating antibodies as the potential basis of novel diagnostic or therapeutic strategies for TB. This proposal describes a five-year research plan to comprehensively investigate the roles of antibodies targeting the mycobacterial glycolipid lipoarabinomannan (LAM) in TB progression in the setting of HIV coinfection. Preliminary data presented indicate that LAM-specific antibodies can predict TB progression in HIV- negative individuals, that they can confer protection against Mtb infection in vitro, and that their recognition of Mtb varies across clinical strains. The LAM epitopes most relevant to immune correlates of TB progression and control of infection, their prevalence across Mtb clinical isolates, and the functional mechanisms of LAM antibody- mediated remain unclear. The studies proposed here aim to 1) define the humoral signatures that predict TB progression in the setting of HIV coinfection, 2) define the breadth and specificity of LAM antibody responses against global Mtb isolates, and 3) define LAM antibody-mediated effector functions that confer antimicrobial control against global Mtb strains. These aims will be approached using an international cohort of HIV-coinfected TB progressors, and make use of innovative methodologies including a powerful systems immunology platform, a panel of synthetic oligosaccharides, a barcoded library of clinical Mtb isolates, and validated in vitro antimicrobial functional assays. The candidate is currently an Instructor in Medicine at Harvard Medical School and an Associate Physician in the Division of Infectious Diseases at Brigham and Women’s Hospital, with an ongoing research commitment of 80% time. The proposal is supported by an expert mentor in humoral immunology, Dr. Galit Alter at the Ragon Institute of MGH, MIT, and Harvard, and an expert co-mentor in mycobacterial diversity, Dr. Sarah Fortune at the Harvard School of Public Health. The training plan unites the candidate’s prior graduate work in glycobiology with specific training in humoral immunology, microbiology, and bioinformatics, as well as ongoing professional development and responsible conduct of research coursework. Completion of this comprehensive training plan will ensure the candidate’s successful development of a unique independent translational research program focused on humoral responses to Mtb glycans.

项目摘要/摘要 减少感染结核分枝杆菌（MTB）的个体中活性结核病的进展 是消除全球结核病的关键组成部分，但它受到现有的差预测价值的阻碍 诊断，繁琐的抗生素方案，对控制免疫力学缺乏了解和 越来越多的研究领域将抗原特异性抗体视为关键 MTB感染控制的生物标志物和介体暗示抗体作为新型的潜在基础 结核病的诊断或治疗策略。 该建议描述了一项五年的研究计划，以全面研究抗体的作用 在HIV的情况下，针对结核病进展中的分枝杆菌糖脂脂肪脂脂脂质脂脂。 共感染。提供的初步数据表明，LAM特异性抗体可以预测HIV- 负个体，他们可以在体外赋予对MTB感染的保护，并且他们对 跨临床菌株的MTB品种。与结核病进展和 控制感染，它们跨MTB临床分离株的患病率以及LAM抗体的功能机制 介导仍不清楚。这里提出的研究目的是1）定义预测结核的体液特征 在HIV共感染的情况下，2）定义LAM抗体反应的宽度和特异性 针对全球MTB分离株，以及3）定义LAM抗体介导的效应子功能，使抗菌剂 控制全球MTB菌株。这些目标将使用国际艾滋病毒感染的国际队列 结核病进展者，并利用包括强大的系统免疫学平台在内的创新方法， 一组合成寡糖，临床MTB分离株的条形码库，并在体外进行了验证 抗菌功能测定。 该候选人目前是哈佛医学院医学教练和同事 杨百翰和妇女医院的传染病分裂的医师，正在进行的研究 承诺为80％。该提案得到了galit Alter博士的体液免疫学专家的支持 在MGH，MIT和哈佛大学的Ragon研究所，以及分枝杆菌多样性的专家莎拉博士 哈佛公共卫生学院的财富。培训计划单位候选人先前的研究生工作 具有特定培训的糖生物学 专业发展和负责任的研究课程。完成这个综合的 培训计划将确保候选人成功发展独特的独立翻译研究 计划着重于对MTB聚糖的体液反应。