Helicobacter pylori infects over half the world's population and is associated with a broad range of gastric maladies including gastritis, peptic ulcer disease, and gastric cancer. Pathogenic strains of H. pylori contain the cag pathogenicity island that encodes a type IV secretion system capable of translocating the bacterial effector protein CagA into host cells. Inside the host cell, CagA binds to a number of host proteins including the phosphatase SHP-2. The molecular pathways activated by CagA in host cells, both dependent and independent of SHP-2, are not well understood. The long-term goal of this project is to determine the mechanisms by which CagA's molecular activity within host cells leads to disruption of host cell signal transduction, loss of epithelial integrity, and ultimately the promotion of carcinogenesis. We have developed a transgenic Drosophila model to study CagA's activity in the retinal epithelium, which is both a model for SHP-2 signal transduction and for epithelial organization. CagA expression in this tissue induces developmental defects that both mimic activation of SHP-2 (specification of excess photoreceptors) and are distinct from SHP-2 activation (disruption of the epithelium and photoreceptor microvilli). In parallel studies we have demonstrated that CagA causes disruption of microvilli in H. pylori infected cultured gastric epithelial cells. Using these two complementary systems, we propose to address the following specific aims: 1. Test the hypothesis that CagA has SHP-2 independent activities in eukaryotic tissues. 2. Test the hypothesis that CagA disrupts epithelial cell microvilli independently of SHP-2 function. 3. Identify genes that mediate CagA function in eukaryotic cells. Stomach cancer is the second leading cause of cancer death worldwide. Over half of all stomach cancers are thought to be caused by infection with the bacterium H. pylori. During H. pylori infection the bacteria translocate a protein, CagA, into stomach cells, which causes changes in the cells that promote cancer. We propose to determine the molecular basis for CagA's effects on stomach cells as a ways to better understand, diagnose, and treat stomach cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Karp, Robert W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Oregon
Organized Research Units
United States
Zip Code
Neal, James T; Peterson, Tracy S; Kent, Michael L et al. (2013) H. pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model. Dis Model Mech 6:802-10
Wandler, Anica M; Guillemin, Karen (2012) Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila. PLoS Pathog 8:e1002939
Goers Sweeney, Emily; Henderson, J Nathan; Goers, John et al. (2012) Structure and proposed mechanism for the pH-sensing Helicobacter pylori chemoreceptor TlpB. Structure 20:1177-88
Yang, Ye; Wandler, Anica M; Postlethwait, John H et al. (2012) Dynamic Evolution of the LPS-Detoxifying Enzyme Intestinal Alkaline Phosphatase in Zebrafish and Other Vertebrates. Front Immunol 3:314
Reid, David W; Muyskens, Jonathan B; Neal, James T et al. (2012) Identification of genetic modifiers of CagA-induced epithelial disruption in Drosophila. Front Cell Infect Microbiol 2:24
Muyskens, Jonathan B; Guillemin, Karen (2011) Helicobacter pylori CagA disrupts epithelial patterning by activating myosin light chain. PLoS One 6:e17856
Sweeney, Emily Goers; Guillemin, Karen (2011) A gastric pathogen moves chemotaxis in a new direction. MBio 2:
Rader, Bethany A; Wreden, Christopher; Hicks, Kevin G et al. (2011) Helicobacter pylori perceives the quorum-sensing molecule AI-2 as a chemorepellent via the chemoreceptor TlpB. Microbiology 157:2445-55
Botham, Crystal M; Wandler, Anica M; Guillemin, Karen (2008) A transgenic Drosophila model demonstrates that the Helicobacter pylori CagA protein functions as a eukaryotic Gab adaptor. PLoS Pathog 4:e1000064