Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, -4 and -9

Eur J Immunol. 2008 Mar;38(3):680-94. doi: 10.1002/eji.200736458.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Mycobacterium tuberculosis / immunology*
  • Myeloid Differentiation Factor 88 / agonists
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / physiology*
  • 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 2 / physiology*
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / physiology*
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / physiology*
  • Tuberculosis / genetics
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • CPG-oligonucleotide
  • Cytokines
  • Ifi1 protein, mouse
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Oligodeoxyribonucleotides
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • GTP-Binding Proteins