The Role of Decay-accelerating Factor as a Receptor for Helicobacter pylori and a Mediator of Gastric Inflammation

Abstract

Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for peptic ulcer disease and distal gastric adenocarcinoma, a process for which adherence of H. pylori to gastric epithelial cells is critical. Decay-accelerating factor (DAF), a protein that protects epithelial cells from complement-mediated lysis, also functions as a receptor for several microbial pathogens. In this study, we investigated whether H. pylori utilizes DAF as a receptor and the role of DAF within H. pylori-infected gastric mucosa. In vitro studies showed that H. pylori adhered avidly to Chinese hamster ovary cells expressing human DAF but not to vector controls. In H. pylori, disruption of the virulence factors vacA, cagA, and cagE did not alter adherence, but deletion of DAF complement control protein (CCP) domains 1-4 or the heavily O-glycosylated serinethreonine-rich COOH-terminal domain reduced binding. In cultured gastric epithelial cells, H. pylori induced transcriptional upregulation of DAF, and genetic deficiency of DAF attenuated the development of inflammation among H. pylori-infected mice. These results indicate that DAF may regulate H. pylori-epithelial cell interactions relevant to pathogenesis.

Helicobacter pyloriInduces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism

“…This in turn may induce the transcription of a novel subset of proinflammatory genes that are exclusively activated in an AP-1-dependent manner during H. pylori infection. One example of this is the decay-accelerating factor (DAF), a H. pylori cellular receptor previously shown to be upregulated following contact with H. pylori (85). Although the DAF promoter contains a B response element, it was found that DAF expression in response to H. pylori was dependent on p38 phosphorylation and totally independent of NF-B (86 -89).…”

Regulation of the Helicobacter pylori Cellular Receptor Decay-accelerating Factor

“…Bacterial Strains-Experiments were performed with the H. pylori cag ϩ strains J166 and 7.13 (13,29). Isogenic cagA, cagE, and cagM null mutants were constructed by insertional mutagenesis using aphA (conferring kanamycin resistance) as previously described (30,31) and were selected on Brucella agar with kanamycin (25 g/ml).…”

“…Level-We previously demonstrated that H. pylori upregulates DAF in vitro (13). To determine whether DAF induction was transcriptionally or post-transcriptionally mediated, the H. pylori cag ϩ strain J166 was co-cultured with MKN28 gastric epithelial cells that had been pretreated with either actinomycin D (inhibitor of transcription) or cycloheximide (inhibitor of translation).…”

“…We recently identified another H. pylori receptor, Decay-accelerating factor (DAF), that is up-regulated after bacterial contact (13). DAF is an intrinsic regulator of complement that is attached to the outer leaflet of the cell membrane by a glycophosphatidylinositol anchor (14).…”

“…We recently demonstrated that DAF influences the inflammatory response to H. pylori as infected DAF-deficient mice developed significantly less severe inflammation compared with infected wild-type mice, suggesting that the interaction between H. pylori and DAF is important for pathogenesis (13).…”