The effect of mixed-strain M. tuberculosis infections on treatment outcomes

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 DESCRIPTION (provided by applicant): Tuberculosis (TB) is responsible for 1.3 million deaths annually and remains the leading cause of death among HIV-infected persons. Tackling the threat of TB will require integrated approaches to improve understanding of the complex factors that drive the epidemic. Academic scholars with expertise in conventional epidemiological methods and the application of cutting-edge molecular methods are needed to address critical gaps in knowledge regarding TB epidemiology. The goal of this Mentored Research Scientist Development Award application is to support Dr. Sanghyuk Shin's development as an independent researcher of TB epidemiology by providing him with intensive training in scientific areas that are critical for understanding this global health threat. During the award period, Dr. Shin will complete his training and submit a R01 application to conduct a large, prospective cohort study on the topic of mixed Mycobacterium tuberculosis infections. Dr. Shin's goal is to become a leading independent university-based researcher in the epidemiology and prevention of TB and TB/HIV coinfection. He previously received excellent training in epidemiology and has demonstrated strong capacity to conduct innovative academic research. The proposed training program is uniquely designed to build on Dr. Shin's background in global health epidemiology and to strengthen his expertise in specific areas relevant to TB. We will focus on the following training topics: 1) the epidemiology of dual infection with HIV and TB; 2) advanced cohort study methodology; 3) molecular epidemiology; and 4) bioinformatics. We will utilize formal coursework and workshops, supervised reading, and practical research experience to achieve the training objectives. Dr. Shin will receive his training under the guidance and supervision of seasoned mentors with extensive track records in TB, HIV, and molecular genetics research. Each mentor has complementary areas of expertise relevant to Dr. Shin's training needs. In addition, Dr. Shin will leverage the vast array of resources available at UCLA to maximize his training experience. UCLA has a long history of improving scientific knowledge with direct relevance to public health and will provide a stimulating environment for Dr. Shin's training. Dr. Shin will have excellent opportunities to learn from world renown experts through numerous seminars, workshops, and courses. In addition, UCLA offers scientific expertise and career development opportunities at the UCLA AIDS Institute, Center for AIDS Research (CFAR), Program in Global Health, Genotyping and Sequencing Core, and the Bioinformatics Core of the Department of Human Genetics. Dr. Shin has designed a highly innovative research proposal to gain practical experience in the four training areas described above. The overall goal of the proposed research is to determine the impact of mixed-strain M. tuberculosis (MTB) infections on TB treatment outcomes. In resource-poor countries, over 20% of TB patients fail treatment, die, or drop out of treatment. Furthermore, patients who complete treatment frequently have a subsequent episode of TB. Recent studies have shown that some patients are infected with multiple strains of MTB (mixed MTB infections). Moreover, patients with mixed MTB infections appear to have higher risk for poor treatment outcomes compared to patients with single-strain infections. The proposed research will provide strong evidence on whether mixed MTB infections actually increase the risk for poor treatment outcomes. Aim 1 of the research project will involve examining existing data from a research database of TB patients in Botswana. We will use existing MTB genetic data to compare the rate of poor treatment outcomes between patients with mixed MTB infections and those with single-strain infections. For a random sample of the patients, we will test stored MTB DNA specimens using the latest gene sequencing technology. The sequencing data will be used to determine whether undetected drug-resistant MTB strains are responsible for poor treatment outcomes among patients with mixed MTB infections. For Aim 2, we will conduct a pilot cohort study to generate preliminary data for a future grant application. The goal of the future application is to determine the extent to which mixed MTB infections are responsible for relapse among TB patient who complete their initial treatment. We will take advantage of a large, ongoing TB research study in Botswana to implement the proposed research. This research will significantly improve the understanding of the clinical effect of mixed MTB infection by using state-of-the-art gene sequencing technology. The study findings could directly impact clinical and public health practice. Given the enormous health burden posed by TB worldwide, the proposed research has substantial implications for global health. This research will also serve as an excellent vehicle for Dr. Shin to strengthen his expertise in scientific areas that are critical for addressing the global threat of TB.