Helicobacter pylori (Hp) infection is the major cause of gastric inflammation, peptic ulcer disease, and gastric cancer. Recent clinical and in vitro data indicate that the Hp outer inflammatory protein, OipA and the cag pathogenicity island (PAI) are involved in disease pathogenesis based on their ability to induce interleukin (IL)-8 in gastric epithelial cells. Our long term goal is to understand the role(s) of OipA, alone and together with the cag PAI, in the pathogenesis of Hp-related diseases.
In AIM 1, we will determine in vitro molecular mechanisms by which OipA, alone and together with the cag PAI, regulate IL-8 gene transcription. Binding sites for the transcription factors nuclear factor-:B (NF-:B), activator protein 1 (AP-1), interferon-stimulated responsive element (ISRE)-like element, and likely interferon-3 activation sequence (GAS) in the IL-8 promoter are involved in regulating IL-8 gene transcription in Hp-infected gastric epithelial cells. We will use polarized gastric epithelial cells with tight junctions (NCI-N87 cells) to overcome the limitations of non-polarized cells. NCI-N87 cells allow us to detect different cell signaling pathways from the apical membrane (early phase of infection) and basolateral membranes (late phase following opening of tight junctions or epithelial-barrier damage). We will focus on the cell surface receptors epidermal growth factor receptor (EGFR) and G protein coupled receptor (GPCR). In vitro models of Hp infection will be used to clarify 1) overall signaling pathways from the cell surface receptor(s) resulting in IL-8 gene transcription, 2) interactions between OipA and the cag PAI, and 3) OipA structures and motifs responsible for IL-8 gene transcription.
In AIM 2, we will determine the correlation between in vitro - in vivo roles of OipA and the cag PAI in gastric injury using Mongolian gerbils and the gp130F759 knock-in mouse model. In gerbils, gastric mucosal transcription factors induced by Hp infection differ with respect to phase and effect on infection (e.g., AP-1 is induced early and results in inflammation and ulceration whereas NF- B and ISRE are induced late and result in atrophy). Our previous results are based on analysis of the whole gastric mucosa. Here, we propose to determine how OipA and the cag PAI induce CXC chemokines using isolated gastric epithelial cells. We will also use mice that lack the Src homology 2 domain of the Src homology 2 phosphatase (SHP-2) binding site on the IL-6 family co- receptor, gp130. In these mice, the signal transducer and activator of transcriptions (STATs) signaling is hyperactivated and SHP-2->AP-1 signaling is absent. Our preliminary data showing that Hp infection results in hyperproliferative tumors in this mouse model will be extended to further clarify the roles of OipA and the cag PAI in the gastroduodenal pathogenesis. We hypothesize that the early phase, where the epithelial cell-cell barrier is intact in vitro, will correlate with acute inflammation in vivo and the late phase, where the epithelial barrier is disrupted in vitro, will correlate with chronic inflammation, ulceration and carcinogenesis (i.e., when the architecture of the gastric epithelium is disrupted in vivo). The innovative focus and strategic approaches described in this application will yield new levels of understanding of the biology of Hp infections.

Public Health Relevance

Helicobacter pylori infection causes gastric inflammation, peptic ulcer disease, and gastric cancer. The work outlined in this application will use human gastric cells and animal models to identify the molecular mechanisms by which Helicobacter pylori virulence factors cause gastric inflammation and subsequent disease. This project will be able to identify novel therapeutic targets for the treatment of Helicobacter pylori infections and prevention of Helicobacter pylori-related diseases.

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
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Waskito, Langgeng Agung; Yih-Wu, Jeng; Yamaoka, Yoshio (2018) The role of integrating conjugative elements in Helicobacter pylori: a review. J Biomed Sci 25:86
Kabamba, Evariste Tshibangu; Tuan, Vo Phuoc; Yamaoka, Yoshio (2018) Genetic populations and virulence factors of Helicobacter pylori. Infect Genet Evol 60:109-116
Binh, Tran Thanh; Tuan, Vo Phuoc; Dung, Ho Dang Quy et al. (2018) Molecular Epidemiology of Helicobacter pylori Infection in a Minor Ethnic Group of Vietnam: A Multiethnic, Population-Based Study. Int J Mol Sci 19:
Khasag, Oyuntsetseg; Boldbaatar, Gantuya; Tegshee, Tserentogtoh et al. (2018) The prevalence of Helicobacter pylori infection and other risk factors among Mongolian dyspeptic patients who have a high incidence and mortality rate of gastric cancer. Gut Pathog 10:14
Gantuya, Boldbaatar; Bolor, Dashdorj; Oyuntsetseg, Khasag et al. (2018) New observations regarding Helicobacter pylori and gastric cancer in Mongolia. Helicobacter 23:e12491
Subsomwong, Phawinee; Miftahussurur, Muhammad; Vilaichone, Ratha-Korn et al. (2017) Helicobacter pylori virulence genes of minor ethnic groups in North Thailand. Gut Pathog 9:56
Miftahussurur, Muhammad; Nusi, Iswan A; Graham, David Y et al. (2017) Helicobacter, Hygiene, Atopy, and Asthma. Front Microbiol 8:1034
Ansari, Shamshul; Yamaoka, Yoshio (2017) Survival of Helicobacter pylori in gastric acidic territory. Helicobacter 22:
Miftahussurur, Muhammad; Cruz, Modesto; Subsomwong, Phawinee et al. (2017) Clarithromycin-Based Triple Therapy is Still Useful as an Initial Treatment for Helicobacter pylori Infection in the Dominican Republic. Am J Trop Med Hyg 96:1050-1059
Sharma, Rabi Prakash; Miftahussurur, Muhammad; Shrestha, Pradeep Krishna et al. (2017) Nepalese Helicobacter pylori Genotypes Reflects a Geographical Diversity than a True Virulence Factor Asian Pac J Cancer Prev 18:2637-2641

Showing the most recent 10 out of 162 publications