ABSTRACT
The role of Toll-like receptors (TLR) and MyD88 for immune responses to Mycobacterium tuberculosis (Mtb) infection remains controversial. To address the impact of TLR-mediated pathogen recognition and MyD88-dependent signaling events on anti-mycobacterial host responses, we analyzed the outcome of Mtb infection in TLR2/4/9 triple- and MyD88-deficient mice. After aerosol infection, both TLR2/4/9-deficient and wild-type mice expressed pro-inflammatory cytokines promoting antigen-specific T cells and the production of IFN-gamma to similar extents. Moreover, TLR2/4/9-deficient mice expressed IFN-gamma-dependent inducible nitric oxide synthase and LRG-47 in infected lungs. MyD88-deficient mice expressed pro-inflammatory cytokines and were shown to expand IFN-gamma-producing antigen-specific T cells, albeit in a delayed fashion. Only mice that were deficient for MyD88 rapidly succumbed to unrestrained mycobacterial growth, whereas TLR2/4/9-deficient mice controlled Mtb replication. IFN-gamma-dependent restriction of mycobacterial growth was severely impaired only in Mtb-infected MyD88, but not in TLR2/4/9-deficient bone marrow-derived macrophages. Our results demonstrate that after Mtb infection neither TLR2, -4, and -9, nor MyD88 are required for the induction of adaptive T cell responses. Rather, MyD88, but not TLR2, TLR4 and TLR9, is critical for triggering macrophage effector mechanisms central to anti-mycobacterial defense.
Subject(s)
Mycobacterium tuberculosis/immunology , Myeloid Differentiation Factor 88/physiology , Toll-Like Receptor 2/physiology , Toll-Like Receptor 4/physiology , Toll-Like Receptor 9/physiology , Tuberculosis/immunology , Animal Structures/microbiology , Animals , Cytokines/genetics , Cytokines/metabolism , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , Gene Expression/drug effects , Immunity, Cellular/genetics , Immunity, Cellular/immunology , Immunity, Innate/genetics , Immunity, Innate/immunology , Interferon-gamma/metabolism , Interferon-gamma/pharmacology , Lipopolysaccharides/pharmacology , Lung/immunology , Lung/metabolism , Lung/microbiology , Macrophages/drug effects , Macrophages/metabolism , Macrophages/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/agonists , Myeloid Differentiation Factor 88/genetics , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Oligodeoxyribonucleotides/pharmacology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/agonists , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/agonists , Toll-Like Receptor 9/genetics , Tuberculosis/genetics , Tuberculosis/microbiology , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Innate resistance against Mycobacterium tuberculosis is thought to depend critically on engagement of pattern recognition receptors on macrophages. However, the relative contribution of these receptors for containing M. tuberculosis infection has remained unexplored in vivo. To address this issue, we infected mice defective in CD14, TLR2, or TLR4 with M. tuberculosis by aerosol. Following infection with 100 mycobacteria, either mutant strain was as resistant as congenic control mice. Granuloma formation, macrophage activation, and secretion of proinflammatory cytokines in response to low-dose aerosol infection were identical in mutant and control mice. However, high-dose aerosol challenge with 2000 CFU M. tuberculosis revealed TLR2-, but not TLR4-defective mice to be more susceptible than control mice. In conclusion, while TLR2 signaling contributes to innate resistance against M. tuberculosis in borderline situations, its function, and that of CD14 and TLR4, in initiating protective responses against naturally low-dose airborne infection is redundant.
