Comparative Genomics and Pathogenesis of Tuberculosis

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DESCRIPTION (provided by applicant): Tuberculosis is a major global health problem. One fourth of the world's tuberculosis cases occur in India, which reports 2 million new cases annually. Recent studies suggest there are a limited number of major phylogenetic lineages of Mycobacterium tuberculosis worldwide. The lineages reported from the Indian subcontinent to date have different genomic properties than the reference strains H37Rv and Erdmann, which are used by most research laboratories around the world. As new diagnostic tests, new anti-TB drugs and new vaccines against tuberculosis are developed, there are compelling reasons to understand and consider the genomic properties, pathogenesis and host-pathogen interactions of the lineages of M. tuberculosis that occur in India and are responsible for a large burden of disease in the world. We hypothesize that the prevalent lineage of M. tuberculosis that occurs in southern India has different pathogenetic characteristics than other lineages. We will test this hypothesis using well-characterized, genotyped clones from a study in the Tiruvallur district, Tamil Nadu state. Specifically, we will 1) characterize the isolates of M. tuberculosis from a population-based molecular epidemiologic study of tuberculosis in southern India using IS6110 RFLP, spoligotyping, genomic deletions and phylogenetic analyses; and 2) characterize the clones of M. tuberculosis in the human host population to identify clone-specific rates of disease. The research plan is a collaborative pilot research project between the Tuberculosis Research Centre (TRC) in Chennai, India and Stanford University, California. We expect this pilot project to 1) address the specific aims outlined above; 2) further the research, training, and technology transfer between the participating scientists and their respective institutions; and 3) generate preliminary data for a future, five- year grant proposal to the NIH that advances research strategies for the Indian subcontinent. By the end of this grant, we will have the tools to survey and identify the predominant clones of M. tuberculosis in the Indo- Oceanic region and to further characterize the pathogenesis of those predominant clones in other experimental in vitro systems.