title: Macrophages recognize the Helicobacter pylori type IV secretion system in the absence of toll-like receptor signalling.
abstract: Helicobacter pylori strains carrying the cag pathogenicity island (cagPAI) provoke an increased inflammatory response, conferring an increased risk of ulcer formation and carcinogenesis. How the immune system recognizes the presence of cagPAI positive strains is yet unclear. By comparing the transcriptional response of wild type and MyD88/Trif(-/-) bone marrow macrophages to infection with H. pylori, we found that the majority of regulated genes were dependent on toll-like receptor (TLR) signalling. To determine the role of TLR-independent responses, we analysed the transcriptome of MyD88/Trif(-/-) bone marrow macrophages at different time points after infection with cagPAI positive versus negative strains. We identified a group of genes that exhibited different kinetic behaviour depending on whether cagPAI was present. Analysis of their gene expression kinetics demonstrated that this responsiveness to cagPAI was observed only in MyD88/Trif(-/-) macrophages. This group of cagPAI-sensing genes was enriched for AU-rich element containing early response genes involved in immune regulation, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Recognition of cagPAI positive strains was found to be mediated by the type IV secretion system (cagT4SS), rather than its effector protein CagA. We hypothesize that anergic macrophages of the gastric mucosa initiate an innate immune response following detection of the T4SS of H. pylori.
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Koch
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D016480:Helicobacter pylori / Q000276:immunology*; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D051193:Toll-Like Receptors / Q000378:metabolism*; D000069319:Type IV Secretion Systems / Q000276:immunology*
chemical_list: D051193:Toll-Like Receptors; D000069319:Type IV Secretion Systems
keywords: AU-rich elements; MyD88/Trif-/-; T4SS; anergic macrophages; cagPAI