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.
Understanding the immunologic and genetic factors that confer protection from tuberculosis is vital to the development of a successful vaccine. CD1a is a recently discovered molecule that activates the immune system after infection with tuberculosis bacteria. I propose to study how CD1a gene expression is controlled, and how genetic variation in CD1a between people affects its function. I will also examine whether CD1a influences the immune response to vaccination and protection from tuberculosis.
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