The Role of CD1a in Protecting Against Human Tuberculosis

CD1a 在预防人类结核病中的作用

• 批准号: 8510564
• 负责人: CHETAN SESHADRI
• 金额: $ 12.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510564
• 关键词: Accident and Emergency department; Acute; Address; Adult; Affect; African; Antigen Presentation; Antigens; Appointment; Bacteria; Basic Science; CD1 Antigens; CD1a antigen; Cell Wall; Chronic; Clinical; Clinical Research; Code; Collaborations; Communicable Diseases; Data; Defect; Dendritic Cells; Development; Diagnostic; Disease susceptibility; Environment; Faculty; Fellowship; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Grant; HIV; Health; Human; Human Genetics; Hypersensitivity; Immune; Immune response; Immune system; Immunologic Factors; Immunologics; Immunology; In Vitro; Individual; Infant; Infection; Inflammatory; International; Laboratories; Lipid Biochemistry; Lipids; Mediating; Medicine; Mentors; Methods; Molecular Biology; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis; Outcome; Peptides; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Physicians; Population; Positioning Attribute; Poverty; Predisposition; Prevalence Study; Production; Publishing; Reporting; Research; Resources; Role; Scientist; Single Nucleotide Polymorphism; South Africa; Specialist; Surface; System; T cell response; T-Lymphocyte; Tanzania; Techniques; Time; Training; Training Programs; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Universities; Vaccinated; Vaccination; Vaccines; Variant; Washington; Work; base; cohort; cytokine; design; early childhood; experience; interest; loss of function; medical schools; meetings; member; monocyte; mycobacterial; novel vaccines; promoter; prospective; response; transcription factor; vaccination against tuberculosis

The applicant is a specialist in infectious diseases with a long-term interest in tuberculosis and international health. His background in basic and clinical research is the basis for the proposed research. He studied basic T-cell immunology at the NIH as a Howard Hughes Research Scholar and lipid antigen presentation by CD1 molecules as a research fellow at Harvard. As a resident, he assisted in a prevalence study of acute and chronic undiagnosed HIV in emergency rooms. He also designed, funded, executed, and published a field trial of in-vitro diagnostics for tuberculosis in Tanzania. His immediate goals are to study the role of lipid antigen presentation in the immunologic and clinical response to vaccination against tuberculosis. He will accomplish this using a number of specialized resources as part of a training program. First, the proposed mentor (Dr. Thomas Hawn) has experience studying common genetic variation in large human cohorts that will be applied for the first time to the CD1 system. Second, he will collaborate with Dr. Willem Hanekom who has established a prospective cohort of 5000 vaccinated infants in South Africa. Third, he will perform immunologic studies in collaboration with Dr. Branch Moody who has identified and synthesized a number of CD1-restricted mycobacterial lipid antigens. The applicant's long term goals are to seek a clinical appointment in a Division of Infectious Diseases at an academic center where he will devote at least 75% effort to managing a lab and/or collaborative clinical study. T-cell responses to M. tuberculosis specific peptides presented in the context of polymorphic MHC molecules have been identified and studied in human populations. However, the cell wall of M. tuberculosis also contains a number of unique lipids that are presented to T-cells in the context of CD1 molecules. Mycobacterium bovis Bacille Calmette-Guerin (BCG) is the only registered TB vaccine currently available and protects against severe forms of TB in early childhood. Whether CD1 antigen specific T-cells are induced after BCG vaccination and correlate with protection from TB is not known. Compared to MHC molecules which are known for their genetic and functional polymorphism, CD1 is considered to display limited variability. The association between genetic variation of the five genes in the CD1 locus (CD1a, CD1b, CD1c, CD1d, and CD1e) and susceptibility to tuberculosis is also not known. The laboratory of the proposed mentor, Dr. Thomas R. Hawn, has identified single nucleotide polymorphisms (SNPs) in innate immune genes and performed functional studies to elucidate loss of function phenotypes. These methods will be used to study the role of CD1a in protection against tuberculosis in South African infants vaccinated with BCG. Preliminary data suggests that some individuals infected with M. tuberculosis fail to express CD1a on the surface of monocyte-derived dendritic cells in response to inflammatory cytokines. Therefore, the applicant will first investigate the mechanism of CD1a gene regulation and expression. Dideoxymycobactin (DDM) is a CD1a-specific mycobacterial antigen identified by Dr. Branch Moody and studied in adults with active tuberculosis, as reported in the preliminary data. In collaboration with Dr. Moody, the applicant will determine if DDM-specific T-cells are induced after BCG vaccination and whether these responses are associated with protection. Finally, the applicant has identified associations between polymorphisms in CD1a and tuberculosis outcome in adults. He proposes to study the effect of these polymorphisms on gene expression and antigen presentation. He will also study the association of these polymorphisms with immunologic and clinical outcome in the BCG vaccinated infants. The lack of immune correlates of protection against tuberculosis has hindered the development of new drugs and vaccines. The work proposed here will directly assess the contribution of CD1-mediated lipid antigen presentation as a correlate of protection against tuberculosis. This work will be performed at the University of Washington School of Medicine in Seattle. The applicant and proposed mentor are in the Division of Allergy and Infectious Diseases which consists of 73 full- time faculty members whose total grant support exceeds $135 million annually. This Division is an ideal environment for training physician-scientists since more than 80% of past fellowship trainees have obtained faculty positions in academic medicine. The applicant proposed research takes advantage of his strong background in T-cell immunology and lipid biochemistry but requires additional training in molecular biology, innate immunology, and human genetics. He has detailed coursework, seminars, and meetings to address these needs. He has also assembled a scientific advisory panel to provide one-on-one expertise. Finally, the proposed mentor has a demonstrated track record with these techniques and has successfully mentored other junior scientists.

申请人是传染病专家，对结核病和国际卫生有长期兴趣。他在基础和临床研究方面的背景是拟议研究的基础。他作为霍华德·休斯学者在美国国立卫生研究院学习基础T细胞免疫学，在哈佛大学作为研究员研究CD1分子的脂类抗原递呈。作为一名住院医生，他协助了急诊室中急性和慢性未诊断艾滋病毒的流行研究。他还设计、资助、执行并发表了一项坦桑尼亚结核病体外诊断的现场试验。他的近期目标是研究脂类抗原呈递在结核病疫苗接种的免疫学和临床反应中的作用。作为培训计划的一部分，他将使用一些专门的资源来实现这一点。首先，被提名的导师(托马斯·霍恩博士)具有研究大规模人类队列中常见基因变异的经验，这将首次应用于CD1系统。其次，他将与Willem Hanekom博士合作，后者已经在南非建立了5000名接种疫苗的婴儿的预期队列。第三，他将与布兰奇·穆迪博士合作进行免疫学研究，后者已经鉴定并合成了一些CD1限制性分枝杆菌脂类抗原。申请人的长期目标是在学术中心的传染病科寻求一个临床职位，在那里他将投入至少75%的精力来管理实验室和/或合作临床研究。 T细胞对结核分枝杆菌特异性多肽的反应在人类群体中已经被鉴定和研究。然而，结核分枝杆菌的细胞壁也含有一些独特的脂类，这些脂类是在CD1分子的背景下呈现给T细胞的。牛分枝杆菌卡介苗(BCG)是目前可用的唯一注册的结核病疫苗，可预防儿童早期的严重形式结核病。目前尚不清楚卡介苗接种后CD1抗原特异性T细胞是否被诱导，并与结核病的保护作用有关。与以遗传和功能多态著称的MHC分子相比，CD1被认为表现出有限的变异性。CD1基因座的5个基因(CD1a、CD1b、CD1c、CD1d和CD1e)的遗传变异与结核病易感性之间的关联也尚不清楚。托马斯·R·霍恩博士的实验室已经确定了先天免疫基因中的单核苷酸多态(SNPs)，并进行了功能研究，以阐明功能表型的丧失。这些方法将被用来研究CD1a在南非接种卡介苗的婴儿预防结核病方面的作用。 初步数据表明，一些结核分枝杆菌感染者未能在单核细胞来源的树突状细胞表面表达CD1a，以响应炎性细胞因子。因此，申请人将首先研究CD1a基因调控和表达的机制。Dideoxymycobactin(DDM)是布兰奇·穆迪博士鉴定的一种CD1a特异性分枝杆菌抗原，初步报道在成人活动性肺结核患者中进行了研究。申请者将与穆迪博士合作，确定在接种卡介苗后是否诱导了DDM特异性T细胞，以及这些反应是否与保护有关。最后，申请人已经确定了CD1a基因多态与成人结核病结局之间的关联。他建议研究这些多态对基因表达和抗原呈递的影响。他还将研究这些基因多态与接种卡介苗的婴儿的免疫学和临床结果之间的关系。缺乏预防结核病的免疫相关因素阻碍了新药和疫苗的开发。这里提出的工作将直接评估CD1介导的脂抗原提呈作为预防结核病的相关性的贡献。 这项工作将在西雅图的华盛顿大学医学院进行。申请者和拟议的导师是过敏和传染病系，该系由73名全职教职员工组成，每年的资助总额超过1.35亿美元。该分部是培训内科科学家的理想环境，因为过去80%以上的研究员受训人员都获得了学术医学方面的教职。申请人提议的研究利用了他在T细胞免疫学和脂质生物化学方面的强大背景，但需要在分子生物学、先天免疫学和人类遗传学方面进行额外的培训。他有详细的课程、研讨会和会议来满足这些需求。他还组建了一个科学顾问小组，提供一对一的专业知识。最后，被推荐的导师在这些技术方面有着良好的记录，并成功地指导了其他初级科学家。