Helicobacter pylori is the strongest identified risk factor for gastric cancer and contact between H. pylori and epithelial cells dysregulates signaling pathways that influence oncogenesis. Thus, our long-term objective is to define molecular pathways induced by pathogenic H. pylori that lead to epithelial responses with carcinogenic potential. We have shown that H. pylori utilizes decay accelerating factor (DAF) as an epithelial receptor, increases its expression in vitro and in vivo, and that DAF deficiency attenuates injury in infected mice. One H. pylori strain-specific determinant that augments cancer risk is the cag pathogenicity island, which translocates peptidoglycan into host cells leading to Nod1 activation. In studies supported by R01 58587, we demonstrated that a rodent-adapted derivative (7.13) of a human H. pylori cag+ strain (B128) rapidly induces gastric cancer in rodents. Utilizing 2D-DIGE and mass spectrometry, we found that the H. pylori protein HP0310 exists as different isoforms in strain 7.13 versus B128. HP0310 deacetylates peptidoglycan, which has focused our current studies on the role of peptidoglycan as a virulence constituent. We now demonstrate that disruption of peptidoglycan synthesis attenuates epithelial cell migration and proliferation in response to H. pylori and abolishes H. pylori-induced DAF expression. H. pylori infection rates typically parallel the prevalence of gastric cancer in specific regions;however, this association is not universal. We have now expanded the scope of our work in collaboration with Dr. Pelayo Correa by examining H. pylori isolates harvested from individuals who reside in either a high-risk or a low-risk region of gastric cancer in Colombia. These studies will allow us to determine if strains harvested from subjects with an enhanced risk for gastric cancer induce carcinogenic epithelial responses. Our hypothesis is that strain-specific proteins expressed by carcinogenic H. pylori aberrantly activate cellular phenotypes that influence disease. Therefore, our specific aims are to: 1. Define pathologic epithelial responses to carcinogenic H. pylori mediated by Nod1 activation. 2. Define alterations in DAF expression that are mediated by Nod1 activation. 3. Determine the role of Nod1 in regulating host inflammatory and injury responses to H. pylori using in vivo and ex vivo genetic models of Nod1 deficiency.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Varga, Matthew Gordon; Peek, Richard M (2017) DNA Transfer and Toll-like Receptor Modulation by Helicobacter pylori. Curr Top Microbiol Immunol 400:169-193
Wang, Y; Liu, L; Moore, D J et al. (2017) An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells. Mucosal Immunol 10:373-384
Xiong, Menghua; Bao, Yan; Xu, Xin et al. (2017) Selective killing of Helicobacter pylori with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides. Proc Natl Acad Sci U S A 114:12675-12680
Zhu, Shoumin; Soutto, Mohammed; Chen, Zheng et al. (2017) Helicobacter pylori-induced cell death is counteracted by NF-?B-mediated transcription of DARPP-32. Gut 66:761-762
Noto, Jennifer M; Peek Jr, Richard M (2017) Helicobacter pylori Makes a Molecular Incision to Gain Epithelial Entry. Cell Host Microbe 22:434-436
Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2017) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut :
Pazos, Alvaro; Kodaman, Nuri; Piazuelo, M Blanca et al. (2017) Draft Genome Sequences of 13 Colombian Helicobacter pylori Strains Isolated from Pacific Coast and Andean Residents. Genome Announc 5:
Suarez, Giovanni; Romero-Gallo, Judith; Sierra, Johanna C et al. (2017) Genetic Manipulation of Helicobacter pylori Virulence Function by Host Carcinogenic Phenotypes. Cancer Res 77:2401-2412
Hardbower, Dana M; Singh, Kshipra; Asim, Mohammad et al. (2016) EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest 126:3296-312
Beckett, Amber C; Piazuelo, M Blanca; Noto, Jennifer M et al. (2016) Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration. Infect Immun 84:3338-3349

Showing the most recent 10 out of 142 publications