Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori

Gastroenterology. 2009 Jun;136(7):2247-57. doi: 10.1053/j.gastro.2009.02.066. Epub 2009 Mar 6.

Abstract

Background & aims: Helicobacter pylori infects half of the world's population, thereby causing significant human morbidity and mortality. The mechanisms by which professional antigen-presenting cells recognize the microbe are poorly understood.

Methods: Using dendritic cells (DCs) from TRIF, MyD88, TLR 2/4/7/9(-/-), and multiple double/triple/quadruple mutant mice, we characterized receptors and pathways mediating innate immune recognition of H pylori.

Results: We identified a MyD88-dependent component of the DC activation program, which was induced by surface TLRs, with TLR2 and to a minor extent also TLR4 being the exclusive surface receptors recognizing H pylori. A second MyD88-dependent component could be blocked in TLR2/4(-/-) DCs by inhibitors of endosomal acidification and depended on intracellular TLRs. We identified TLR9-mediated recognition of H pylori DNA as a principal H pylori-induced intracellular TLR pathway and further showed that H pylori RNA induces proinflammatory cytokines in a TLR-dependent manner. Microarray analysis showed complementary, redundant, and synergistic interactions between TLRs and additionally revealed gene expression patterns specific for individual TLRs, including a TLR2-dependent anti-inflammatory signature. A third component of the DC activation program was primarily composed of type I interferon-stimulated genes. This response was MyD88 and TRIF independent but was inducible by RIG-I-dependent recognition of H pylori RNA.

Conclusions: These results provide novel comprehensive insights into the mechanisms of H pylori recognition by DCs. Understanding these processes provides a basis for the rational design of new vaccination strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Cells, Cultured
  • DNA, Bacterial / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Helicobacter Infections / diagnosis
  • Helicobacter pylori / genetics
  • Helicobacter pylori / immunology*
  • Immunity, Innate / genetics
  • Immunity, Innate / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • RNA, Bacterial / metabolism
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / immunology*
  • Receptors, Pattern Recognition / metabolism
  • Sensitivity and Specificity
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Toll-Like Receptors / deficiency

Substances

  • DNA, Bacterial
  • RNA, Bacterial
  • Receptors, Pattern Recognition
  • Toll-Like Receptors