(provided by the applicant): It is projected that a total of 225 million new cases of tuberculosis will occur between 1998 and 2030. The outcome of primary infection with Mycobacterium tuberculosis (MTB) varies and, in immunocompetent hosts, imparts only a 10 percent lifetime risk of developing clinical disease. The significant variation in tuberculosis susceptibility among immunocompetent individuals remains unexplained. Differences in the outcome of tuberculosis infection in the setting of similar risk factors support a significant role of the host genetic background in predisposition to progression towards clinical disease. Therefore, identification of genetic factors associated with susceptibility to tuberculosis will have important implications for controlling the disease. We use a mouse experimental model of infection with virulent strain of MTB to characterize genes that are responsible for control of tuberculosis infection in immunocompetent hosts. We have identified and mapped to a 2 cM interval on mouse chromosome 1 a novel locus (sst1) that significantly contributes to control of growth of virulent MTB primarily in the lungs. Observations on its phenotypic expression demonstrate that genetic mechanisms controlling infection with virulent MTB are distinct from those that control an avirulent vaccine strain of M bovis BCG. Having generated a set of sst1-congenic inbred strains of mice, we propose to use them (1) to isolate the sst1-candidate genes by positional cloning; (2) to identify genetic polymorphism responsible for tuberculosis susceptibility; (3) to identify cells and functional pathways affected by the sst1 polymorphism. The proposed project will identify the nature and mechanism of action of the sst1 in mice, which in the future should permit isolation of its human homologue and the analysis of its role in tuberculosis susceptibility in humans. The understanding of genetically determined mechanisms that operate during the course of tuberculosis infection in the lung will provide new insights into the pathogenesis of tuberculosis and suggest improved strategies for treatment and prevention of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI049421-01A1
Application #
6434208
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
2001-09-30
Project End
2006-06-30
Budget Start
2001-09-30
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$364,050
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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Pan, Hui; Mostoslavsky, Gustavo; Eruslanov, Evgeny et al. (2008) Dual-promoter lentiviral system allows inducible expression of noxious proteins in macrophages. J Immunol Methods 329:31-44
Pan, Hui; Yan, Bo-Shiun; Rojas, Mauricio et al. (2005) Ipr1 gene mediates innate immunity to tuberculosis. Nature 434:767-72
Boyartchuk, Victor; Rojas, Mauricio; Yan, Bo-Shiun et al. (2004) The host resistance locus sst1 controls innate immunity to Listeria monocytogenes infection in immunodeficient mice. J Immunol 173:5112-20