The Role of CD1a in Protecting Against Human Tuberculosis

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这项拟议研究的基础。他作为霍华德休斯研究学者在美国国立卫生研究院学习基础t细胞免疫学，并在哈佛大学担任研究员，研究CD1分子的脂质抗原呈递。作为一名住院医生，他在急诊室协助进行了一项急性和慢性未确诊艾滋病毒的流行研究。他还在坦桑尼亚设计、资助、执行并发表了一项结核病体外诊断的实地试验。他的近期目标是研究脂质抗原呈递在结核病疫苗免疫和临床反应中的作用。作为培训计划的一部分，他将使用一些专门的资源来完成这项工作。首先，提议的导师（Dr. Thomas Hawn）有在大型人类群体中研究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，后者已在南非建立了一个由5000名接种疫苗的婴儿组成的前瞻性队列。第三，他将与Branch Moody博士合作进行免疫学研究，后者已经鉴定并合成了许多限制cd1的分枝杆菌脂质抗原。申请人的长期目标是在学术中心的传染病部门寻求临床任命，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。

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.