Comparative Genomics and Pathogenesis of Tuberculosis

描述（由申请人提供）：结核病是一个主要的全球健康问题。世界上四分之一的结核病病例发生在印度，每年报告200万新病例。最近的研究表明，世界范围内结核分枝杆菌的主要系统发育谱系数量有限。迄今为止从印度次大陆报告的谱系与世界上大多数研究实验室使用的参考菌株H37Rv和Erdmann具有不同的基因组特性。随着新的诊断测试、新的抗结核药物和新的结核病疫苗的开发，有令人信服的理由了解和考虑发生在印度并造成世界上很大疾病负担的结核分枝杆菌谱系的基因组特性、发病机制和宿主-病原体相互作用。

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.