Progression of Pulmonary Tuberculosis and Efficiency of Bacillus Calmette-Guérin Vaccination Are Genetically Controlled via a Common sst1-Mediated Mechanism of Innate Immunity

Abstract

Using a mouse model for genetic analysis of host resistance to virulent Mycobacterium tuberculosis, we have identified a genetic locus sst1 on mouse chromosome 1, which controls progression of pulmonary tuberculosis. In vitro, this locus had an effect on macrophage-mediated control of two intracellular bacterial pathogens, M. tuberculosis and Listeria monocytogenes. In this report, we investigated a specific function of the sst1 locus in antituberculosis immunity in vivo, especially its role in control of pulmonary tuberculosis. We found that the sst1 locus affected neither activation of Th1 cytokine-producing T lymphocytes, nor their migration to the lungs, but rather controlled an inducible NO synthase-independent mechanism of innate immunity. Although the sst1S macrophages responded to stimulation with IFN-γ in vitro, their responsiveness to activation by T cells was impaired. Boosting T cell-mediated immunity by live attenuated vaccine Mycobacterium bovis bacillus Calmette-Guérin or the adoptive transfer of mycobacteria-activated CD4+ T lymphocytes had positive systemic effect, but failed to improve control of tuberculosis infection specifically in the lungs of the sst1S animals. Thus, in the mouse model of tuberculosis, a common genetic mechanism of innate immunity mediated control of tuberculosis progression in the lungs and the efficiency of antituberculosis vaccine. Our data suggest that in immunocompetent humans the development of pulmonary tuberculosis and the failure of the existing vaccine to protect against it, in some cases, may be explained by a similar defect in a conserved inducible NO synthase-independent mechanism of innate immunity, either inherited or acquired.

Dominant Role of the sst1 Locus in Pathogenesis of Necrotizing Lung Granulomas during Chronic Tuberculosis Infection and Reactivation in Genetically Resistant Hosts

“…In fact, formation of necrotic microfoci preceded the rampant multiplication of the bacteria in the lungs of the sst1-susceptible C3HeB/ FeJ mice. 18 In the present study of B6.C3H-sst1 mice, we have observed well-organized necrotic lesions in the lungs, which contained ϳ10 7 CFU of M. tuberculosis (Figure 1, B and D). Notably, a bacterial burden of similar magnitude does not cause necrosis in the lungs of the sst1-resistant congenic mice of either C3H or B6 genetic backgrounds.…”

“…We also analyzed the kinetics of gene expression in tuberculosis lung lesions of the sst1 congenic mice and found no evidence that Th1/Th2 dysbalance was responsible for phenotypic expression of the sst1 locus in our model. 18 Moreover, we have demonstrated that lung necrosis occurred in the sst1-susceptible scid mice even after adoptive transfer of mycobacteria-specific Th1 cells isolated from BCG-immunized sst1-resistant congenic mice. 18 In addition, we have shown that inactivation of transcription factor tbet that controls Th1 differentiation, increases susceptibility of the resistant B6 mice to tuberculosis systemically, but does not cause necrosis of tuberculosis lung lesions.…”

“…The preparation of mycobacterial suspensions has been described elsewhere. 18 Briefly, M. tuberculosis was grown to mid-log phase in Middlebrook 7H9 liquid medium (BD Biosciences, Franklin Lakes, NJ) enriched with 10% OADC (oleic acid/albumin/catalase/dextrose), 0.05% Tween 80, and 0.5% glycerol, washed, resuspended in PBS containing 1% fetal calf serum and 10% glycerol, aliquoted, and frozen at Ϫ80°C until use. For infection of mice, the frozen stock was melted, sonicated, and diluted in PBS containing 0.05% Tween 80.…”

An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

“…tuberculosis suspensions were used as previously described (36). In short, M. tuberculosis (Erdman strain; Trudeau Institute, Saranac Lake, NY) cultures were grown to midlog phase in Middlebrook 7H9 medium (BD Biosciences, Franklin Lakes, NJ) (10% oleic acid/albumin/dextrose/ catalase [OADC; Difco], 0.05% Tween 80 [Sigma-Aldrich], and 0.5% glycerol [Sigma-Aldrich]).…”

Inflammation and Immunopathogenesis of Tuberculosis Progression

“…A role for host genetic factors in the control of inflammation and TB progression was directly demonstrated in the studies by Kramnik's group (Pan et al, 2005;Yan et al, 2007). The authors identified sst1 genetic loci on mouse chromosome 1 that controls progression of pulmonary TB.…”