Tuberculosis remains a significant threat to humans with approximately 8 million new cases per year worldwide and fatality rate of 50%, when it is untreated or drug-resistant. At present, an understanding of how virulent Mycobacterium tuberculosis (MTB) deceives and defeats the immune system in susceptible individuals, and thus the ability to predict of which individuals are at risk and to develop directed therapeutic interventions, is lacking, which limits our progress towards eradication of tuberculosis. Existence of effective mechanisms of host resistance to tuberculosis is demonstrated by the fact that a significant proportion of individuals that have been exposed to MTB remain disease-free. It is currently estimated that less than 10% of the exposed individuals develop clinical disease. The majority of patients that suffer from tuberculosis have no overt immunodefeciency and their susceptibility is likely to be due to combinatorial effects of multiple genetic and environmental factors.
Genetic variation in the host populations has been shown to be one of the most important variables that determines host resistance to tuberculosis in both natural human hosts and experimental animal models of the infection. Mice provide an excellent model system to explore the relationship between genetic variation in host populations and infection outcome. The ability to control environmental exposure and to manipulate genomes affords obvious experimental potential not available in direct human studies and in addition, many classical inbred strains are known to have extreme susceptibility and resistance phenotype. Using mouse model of infection with virulent M. tuberculosis, we have previously identified one genetic locus (sst1), at which the susceptible polymorphic allele did not confer an overt immunodeficiency, but rather specifically affected progression of lung tuberculosis. Recently, we have found that the sst1 locus controls macrophage-mediated mechanism of innate immunity to intracellular pathogens MTB and Listeria monocytogenes and identified a novel gene Ipr1 (intracellular pathogen resistance 1) within the sst1 locus using positional cloning strategy. We have also mapped four additional genetic loci contributing to tuberculosis resistance in our model. Identification of polymorphic genes within the new loci and understanding specific contribution of each genetic determinant to host resistance to tuberculosis will lead to further untangling of complex interactions of MTB with its host and may provide theoretical basis for rational interventions.
Currently our research is focused on identification of polymorphic genes that control host resistance to tuberculosis; development of methodologies to test innate immunity to tuberculosis for predicting individual susceptibility to tuberculosis in experimental models and, in the future, in human populations; biochemical characterization of the Ipr1 protein function in macrophages in order to develop optimal strategies for correcting macrophage-mediated mechanisms of innate immunity to intracellular pathogens.