Toll-like Receptor 2, Vitamin D, and Extrapulmonary Tuberculosis

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DESCRIPTION (provided by applicant): Tuberculosis (TB) is a global health emergency. The World Health Organization estimated that approximately 9.3 million people worldwide were diagnosed with TB in 2007 and 2 million persons died. TB represents an interesting paradox: while one-third of the world's population is estimated to be infected with Mycobacterium tuberculosis, only 5-10% of infected persons go on to develop clinical manifestations of TB. Extrapulmonary TB is likely a marker of underlying immune compromise. The candidate's mentor has performed studies showing that persons with previous extrapulmonary TB appear to have an innate immune defect compared to persons with previous pulmonary TB and latent M. tuberculosis infection. Further study of the immune response of persons with previous extrapulmonary TB could provide clues to the immune factors that predispose a person to progress from latent M. tuberculosis infection to clinical disease and contribute to TB prevention efforts by identifying potential targets for TB vaccines. Emerging evidence suggests that pathogen recognition receptors called Toll-like receptors (TLRs), specifically TLR2, and vitamin D play a major role in the immune response to M. tuberculosis. In this study, two Specific Aims will be addressed: (1) to evaluate the quantity and function of TLR2 in persons with previous extrapulmonary TB and (2) to measure the quantity and function of the vitamin D receptor and vitamin-D mediated immune activation in persons with previous extrapulmonary TB. Measurements of quantity and function will be performed using polymerase chain reaction (PCR) and flow cytometry. Results will be compared to results obtained from persons with previous pulmonary TB, persons with latent M. tuberculosis infection, and healthy controls who are not infected with M. tuberculosis (PPD negative). The Aims will be investigated using an in vitro model of macrophage stimulation and infection with M. tuberculosis. The candidate has a strong background in clinical research, having obtained her Masters of Public Health and completed several TB epidemiologic studies. This award will support her while she achieves her short term career goal of expanding her knowledge of the immune response to M. tuberculosis, while establishing a strong foundation in translational immunologic research from which to attain her long term goal of becoming an independent and productive translational investigator. Her two primary Career Development Aims are: (1) to strengthen her existing knowledge and acquire new expertise in immunology and translational research and (2) to refine her scientific writing skills in manuscripts and grants to successfully compete for long-term research support through RO1 funding from NIH. The candidate plans to augment her immunology and research skills through hands-on training in the laboratory, participation in several didactic courses in advanced immunology and research skills, and attendance of national and international scientific meetings which will be favorable for networking and collaborating with investigators with shared interests. She will achieve her second Aim through didactic coursework in scientific writing as well as participation in available writing workshops and internal grant review mechanisms available at Vanderbilt University Medical Center. Her environment at Vanderbilt University Medical Center is conducive to her aspirations. She is supported by her primary mentor, Dr. Timothy Sterling, who is an internationally recognized expert in the area of TB research, has successfully mentored young physician-scientists who have gone on to productive research careers in academic medicine, and has the resources available to support her research efforts. Her co-mentor, Dr. Spyros Kalams, is an accomplished immunologist and has provided guidance in the immunology lab. She also is mentored by a committee consisting of highly successful basic and translational researchers at Vanderbilt with diverse research interests who will help guide her career development. The resources available to the candidate include state-of-the-art laboratory facilities and equipment as well as core laboratories with advanced technology. In addition to technical resources, the candidate has access to unique resources at Vanderbilt University Medical Center made possible by the Clinical and Translational Science Award (CTSA) such as the Clinical Research Center, the Vanderbilt Institute for Clinical and Translational Research, and the Clinical and Translational Scientist Development program, the educational component of the CTSA. The university has shown invested interest in the candidate by supporting her through the Vanderbilt Physician Scientist Development Program (VPSD), a competitive intramural funding mechanism that serves as a "bridge" to extramural funding (ie K award). The current proposal has important implications to the field of TB prevention and vaccinology, and this award will allow the candidate to build on her strong foundation of clinical TB research and develop new skills in translational research and transition to the next phase of her career.