Progression of pulmonary tuberculosis and efficiency of bacillus Calmette-Guérin vaccination are genetically controlled via a common sst1-mediated mechanism of innate immunity.
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-gamma 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.
Yan
Bo-Shiun
BS
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Pichugin
Alexander V
AV
Jobe
Ousman
O
Helming
Laura
L
Eruslanov
Evgeniy B
EB
Gutiérrez-Pabello
José A
JA
Rojas
Mauricio
M
Shebzukhov
Yuriy V
YV
Kobzik
Lester
L
Kramnik
Igor
I
D000818:Animals; D001500:BCG Vaccine / Q000276:immunology / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D002875:Chromosomes / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci / Q000235:genetics* / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D014611:Vaccination
D001500:BCG Vaccine; D016207:Cytokines; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse