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Progression of Pulmonary Tuberculosis and Efficiency of Bacillus Calmette-Guérin Vaccination Are Genetically Controlled via a Common sst1-Mediated Mechanism of Innate Immunity¹

Bo-Shiun Yan^*, Alexander V. Pichugin^*, Ousman Jobe^*, Laura Helming^2,*, Evgeniy B. Eruslanov^*, José A. Gutiérrez-Pabello^*, Mauricio Rojas^*,, Yuriy V. Shebzukhov^*, Lester Kobzik and Igor Kramnik^3,*

^* Department of Immunology and Infectious Diseases and Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115; and Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia

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 sst1^S macrophages responded to stimulation with IFN- 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 sst1^S 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI49421 and P01 AI056296 (to I.K.).

² Current address: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX13RE, U.K.

³ Address correspondence and reprint requests to Dr. Igor Kramnik, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 667 Huntington Avenue, Boston, MA 02115. E-mail address: ikramnik{at}hsph.harvard.edu

⁴ Abbreviations used in this paper: MTB, Mycobacterium tuberculosis; BCG, bacillus Calmette Guérin; BMDM, bone marrow-derived macrophage; iNOS, inducible NO synthase; PPD, purified protein derivative; MOI, multiplicity of infection.