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: 8719921
• 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/8719921
• 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.

申请人是对结核病和国际健康的长期感兴趣的传染病专家。他在基础和临床研究方面的背景是拟议研究的基础。他在NIH研究了基本的T细胞免疫学，当时是霍华德·休斯（Howard Hughes）研究学者和CD1分子的脂质抗原表现，是哈佛大学的研究研究员。作为居民，他协助对急诊室急性和慢性未诊断的艾滋病毒的普遍研究。他还设计，资助，执行和发布了坦桑尼亚结核病诊断的现场试验。他的直接目标是研究脂质抗原表现在对结核病疫苗接种的免疫和临床反应中的作用。作为培训计划的一部分，他将使用许多专业资源来实现这一目标。首先，拟议的导师（托马斯·霍恩（Thomas Hawn）博士）具有研究大型人类人群中常见遗传变异的经验，这将首次应用于CD1系统。其次，他将与Willem Hanekom博士合作，Willem Hanekom博士在南非建立了5000名接种疫苗的婴儿。第三，他将与穆迪博士合作进行免疫研究，后者已经确定并合成了许多CD1限制的分枝杆菌脂质抗原。申请人的长期目标是在一个学术中心寻求传染病部门的临床任命，他将至少努力管理实验室和/或协作临床研究。 在人群中已经鉴定出来并研究了在多态性MHC分子中提出的对结核分枝杆菌特异性肽的T细胞反应。然而，结核分枝杆菌的细胞壁还包含许多在CD1分子中呈现给T细胞的独特脂质。牛分枝杆菌巴基氏菌（Bacille Calmette-Guerin）（BCG）是目前唯一可用的结核病疫苗，可在童年时期预防严重的结核病。 CD1抗原特异性T细胞是否在BCG疫苗接种后诱导并与TB的保护相关。与以其遗传和功能多态性闻名的MHC分子相比，CD1被认为显示出有限的变异性。 CD1基因座（CD1A，CD1B，CD1C，CD1D和CD1E）中五个基因的遗传变异与结核病的敏感性之间的关联也不知道。拟议的导师托马斯·R·霍恩（Thomas R. Hawn）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性（SNP），并进行了功能研究以阐明功能表型的丧失。这些方法将用于研究CD1A在防止BCG接种疫苗的南非婴儿防止结核病中的作用。 初步数据表明，一些感染结核分枝杆菌的个体无法在单核细胞衍生的树突状细胞表面表达CD1A，以响应炎症性细胞因子。因此，申请人将首先研究CD1A基因调节和表达的机制。如初步数据中所述，二氧氧化甲状腺素（DDM）是由Branch Moody博士鉴定的CD1a特异性分枝杆菌抗原，并在具有活性结核病的成年人中进行了研究，如初步数据所述。申请人将与穆迪博士合作，确定在BCG疫苗接种后是否诱导了DDM特异性T细胞，以及这些反应是否与保护有关。最后，申请人确定了CD1A中多态性与成人结核病结果之间的关联。他建议研究这些多态性对基因表达和抗原表现的影响。他还将研究BCG接种婴儿中这些多态性与免疫学和临床结果的关联。缺乏针对结核病保护的免疫相关性阻碍了新药和疫苗的发展。这里提出的工作将直接评估CD1介导的脂质抗原表现的贡献，这是针对结核病的保护。 这项工作将在西雅图华盛顿大学医学院进行。申请人和拟议的导师是过敏和传染病的部门，由73名全职教职员工组成，他们的总赠款支持每年超过1.35亿美元。该部门是培训医师科学家的理想环境，因为过去80％以上的奖学金学员已经获得了学术医学领域的职位。申请人提出的研究利用了他在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，以满足这些需求。他还组建了一个科学咨询小组，以提供一对一的专业知识。最后，拟议中的导师通过这些技术有了记录，并成功地指导了其他初级科学家。