TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins

J Immunol. 2014 Oct 1;193(7):3736-45. doi: 10.4049/jimmunol.1401413. Epub 2014 Aug 29.

Abstract

Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host-pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB-regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2-associated responses were preserved. Experiments using leukocytes from IL-1R-associated kinase-4-deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R-associated kinase-4-mediated inflammatory responses to S. pneumoniae.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Bacterial / genetics
  • Gene Expression Regulation, Bacterial / immunology*
  • HEK293 Cells
  • Humans
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / pathology
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / immunology
  • Lipoproteins / genetics
  • Lipoproteins / immunology*
  • Macrophages / immunology
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Pneumonia, Pneumococcal / genetics
  • Pneumonia, Pneumococcal / immunology*
  • Pneumonia, Pneumococcal / pathology
  • Primary Immunodeficiency Diseases
  • Streptococcus pneumoniae / genetics
  • Streptococcus pneumoniae / immunology*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Bacterial Proteins
  • Lipoproteins
  • NF-kappa B
  • TLR2 protein, human
  • TLR4 protein, human
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Irak4 protein, mouse

Supplementary concepts

  • IRAK4 Deficiency