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Title page for ETD etd-03192008-130420

Type of Document Dissertation
Author O'Brien, Daniel Patrick
Author's Email Address obriendp21@gmail.com
URN etd-03192008-130420
Title Delineation of a novel Helicobacter pylori receptor, decay-accelerating factor
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Richard M. Peek Committee Chair
David Brent Polk Committee Member
Mary Zutter Committee Member
Timothy Cover Committee Member
  • Adenocarcinoma -- Etiology
  • Helicobacter pylori infections -- Pathophysiology
  • Helicobacter
  • pylori
  • cd55
  • decay-accelerating factor
  • inflammation
  • cancer
  • DAF
  • Stomach -- Cancer -- Etiology
  • Host-bacteria relationships
Date of Defense 2008-03-14
Availability unrestricted
Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and infection with Helicobacter pylori is the strongest known risk factor for this malignancy. Adherence of H. pylori to gastric epithelial cells is critical for induction of gastric injury; therefore, the objective of this dissertation was to investigate the molecular pathways induced by pathogenic H. pylori that lead to epithelial cellular responses with carcinogenic potential. We hypothesized that a host factor that may influence aberrant responses to H. pylori is decay-accelerating factor (DAF), a glycosylphosphatidylinositol (GPI)-anchored protein that primarily functions by dissociating C3/C5 convertases on the host-cell surface. DAF serves as a cellular receptor for several pathogens, and DAF expression is increased within H. pylori-infected human gastric tissue.

We show that H. pylori adheres significantly more avidly to cells that stably express human DAF compared to vector alone. In vitro, H. pylori induces DAF up-regulation in gastric epithelial cells, and genetic deficiency of DAF attenuates the development of inflammation in H. pylori-infected mice. Utilizing an in vitro coculture model we demonstrate that DAF is transcriptionally up-regulated by H. pylori, which was attenuated by disruption of a structural component of the cag secretion system (cagE). H. pylori-induced expression of DAF was dependent upon activation of the p38 MAP kinase pathway, but not NF-êB. In vivo, mice infected with wild-type H. pylori demonstrated significantly increased DAF expression in the gastric epithelium versus uninfected controls or mice infected with an H. pylori cagE- isogenic mutant strain.

Collectively these studies have defined DAF as a novel receptor for H. pylori that is an important mediator of the inflammatory response in vivo. We also demonstrated that H. pylori cag+ strains induced the up-regulation of this receptor in vitro and in vivo in a cag-dependent manner, representing the first evidence of regulation of an H. pylori host receptor by the cag pathogenicity island. These studies have provided a foundation for further investigation of an H. pylori receptor that has important implications for our understanding of disease progression and clinical outcome.

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