Tuberculosis remains a significant public health problem, despite substantial effort to develop new drugs and vaccines in recent years. Host variation in terms of susceptibility to the infection is a major impediment to the development of universally efficient prevention and treatment strategies. This variation is partially explained by the genetic factors. In our studies mouse model of infection with virulent Mycobacterium tuberculosis (MTB) is used to dissect complex genetic control of host resistance to MTB and reveal genes, which strongly influence progression of tuberculosis infection in vivo. Our studies demonstrate that dramatic differences in tuberculosis susceptibility of two immunocompetent mouse strains C3HeB/FeJ and C57BL/6J mice are due to effects of several genetic loci and their epistatic interactions. To date, we have mapped nine tuberculosis resistance loci, dissected the sst1 locus and identified the Ipr1 gene by positional cloning. Synergisitic interactions of the sst1 with a novel locus on mouse chromosome 7 (Chr7) represent a major genetic component in our model, which accounts for about 50% of the variation between the parental strains. The cumulative effect of the two B6-derived resistance loci was remarkably stronger than the sum of their individual effects, providing the first direct experimental evidence of epistatic gene interactions in control of host resistance to MTB. Together the two loci increased the survival of the extremely susceptible C3HeB/FeJ mice from one month to 5 - 6 months post infection, greatly improved control of MTB growth and decreased lung inflammation. In this application we propose genetic and functional characterization of the Chr7 locus to identify causal gene using positional cloning and reveal its specific role in control of host resistance of tuberculosis infection. The candidate region will be reduced to 0.5 - 2 Mb interval using a set of subcongenic strains that we have developed. Haplotype structure, gene expression pattern and sequence analysis of the minimal candidate region will be used to identify top candidate genes. Functional analysis of the candidate gene will be performed using in vitro and in vivo assays to obtain definitive proof for its role in host resistance to MTB and characterize pathways that the candidate gene controls at molecular, cellular and whole organism levels. This will lead to a better understanding of how different pathways interact to produce resistant or susceptible phenotypes in immunocompetent hosts, an exploration of these pathways in humans and potentially provide molecular targets for correction of the susceptible phenotypes.

Public Health Relevance

Tuberculosis remains a significant public health problem. To reduce the disease burden we must improve our understanding of how the pathogen destroys lungs of immunocompetent individuals and reveal environmental and genetic factors responsible for big differences among individuals in resistance to tuberculosis. We use genetic analysis in experimental mouse model of infection to identify genes, which effects strongly influence progression of tuberculosis infection in the lungs and have found two major host resistance loci, which synergistic effect dramatically reduce lung pathology and increase survival of the tuberculosis infected mice. We have previously characterized one of those loci, sst1, and found a candidate gene, which mediates innate immunity to tuberculosis. In this application we propose genetic and functional dissection of the second locus on chromosome 7 to isolate novel host resistance gene and reveal its function in control of tuberculosis infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059836-13
Application #
7749019
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Peavy, Hannah H
Project Start
1997-09-30
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
13
Fiscal Year
2010
Total Cost
$422,500
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Leu, Jia-Shiun; Chen, Mei-Ling; Chang, So-Yi et al. (2017) SP110b Controls Host Immunity and Susceptibility to Tuberculosis. Am J Respir Crit Care Med 195:369-382
He, Xianbao; Berland, Robert; Mekasha, Samrawit et al. (2013) The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism. PLoS Pathog 9:e1003569
Apt, Alexander; Kramnik, Igor (2009) Man and mouse TB: contradictions and solutions. Tuberculosis (Edinb) 89:195-8
Nalbandian, A; Yan, B-S; Pichugin, A et al. (2009) Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene 28:1928-38
Aryee, Martin J; Gutierrez-Pabello, Jose A; Kramnik, Igor et al. (2009) An improved empirical bayes approach to estimating differential gene expression in microarray time-course data: BETR (Bayesian Estimation of Temporal Regulation). BMC Bioinformatics 10:409
Pichugin, Alexander V; Yan, Bo-Shiun; Sloutsky, Alex et al. (2009) Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol 174:2190-201
Sissons, J; Yan, B-S; Pichugin, A V et al. (2009) Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1. Genes Immun 10:37-46
Kumar, Ashwani; Deshane, Jessy S; Crossman, David K et al. (2008) Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon. J Biol Chem 283:18032-9
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
Yan, B-S; Kirby, A; Shebzukhov, Y V et al. (2006) Genetic architecture of tuberculosis resistance in a mouse model of infection. Genes Immun 7:201-10

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