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 serine-threonine-rich COOH-terminal domain reduced binding. In cultured gastric epithelial cells, H. pylori induced transcriptional up-regulation 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.
Highlights
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
Expression of Human Decay-accelerating factor (DAF) Increases Cellular Binding of H. pylori in Vitro—To determine whether DAF mediates H. pylori binding to host cells, we used Chinese hamster ovary (CHO) cells stably transfected with a human DAF cDNA or vector alone (Fig. 1A) and co-cultured the transfectants with a well characterized H. pylori strain, J166, which is transformable and binds well to gastric epithelial cells [15, 43]
Our current experiments identify a new mechanism that may contribute to H. pylori pathogenesis
Summary
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. 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. Helicobacter pylori induces an inflammatory response in the stomach that persists for decades and biological costs incurred by chronic infection include an increased risk for peptic ulceration, gastric adenocarcinoma, and non-Hodgkins lymphoma of the stomach [1, 2]. The presence of the cag island influences the topography of colonization, as H. pylori cagϪ strains predominate within the mucus gel layer, while cagϩ strains are found immediately adjacent to epithelial cells [13] Concordant with these properties, H. pylori strains that harbor a functional cag island are associated with an increased risk for ulcer disease and gastric cancer compared with cagϪ strains [1]
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