Helicobacter pylori chronically colonizes over half of the world's human population and causes diseases such as gastritis, ulcer disease and gastric carcinoma. H. pylori colonizes within the stomach, where it encounters large fluctuations in pH, iron availability and other environmental factors. Because of this dynamic niche and due to H. pylori's high success rate in long-term colonization, the bacterium must be adept at regulating gene expression. We previously showed that expression of the gene that encodes the Ferric Uptake Regulator (Fur) was altered upon exposure of H. pylori to acidic pH and upon iron limitation. Thereafter, our and other groups have shown that Fur is a crucial regulatory factor that is required for survival of H. pylori at low pH, upon nutrient (iron) deprivation, and within oxidative, nitrosative and osmotic stress conditions. Moreover, and perhaps most importantly, we have shown that Fur-mediated regulation is crucial for H. pylori colonization and disease;Fur mutant strains show altered dynamics of colonization in the gerbil model of infection as well as significant attenuation in development of inflammation and gastric cancer. Additionally, our subsequent studies suggest that the effect on disease may be due to a role for Fur in activation of expression of cagA, which encodes a type IV secreted effector protein that is crucial for cancer development. Herein, we propose to characterize the process of Fur-mediated activation of expression of cagA and examine expression and delivery of CagA in vivo, define the role of identified Fur-regulated genes in stress adaptation, colonization and disease development and to determine the role of Fur in expression of H. pylori small RNA (sRNA) species as well as the contribution of these sRNA species to gene expression. We predict that our work will continue to shed significant insight into the process by which gene regulation is mediated in H. pylori as well as help to define how adaptation relates to infection and ultimate disease development by this important human pathogen. These studies will fill a fundamental gap in knowledge concerning the process of adaptation and regulation in H. pylori and should provide potential new therapeutic targets for H. pylori.

Public Health Relevance

More than 50% of the world's human population is infected with the pathogen Helicobacter pylori. Thus, H. pylori-associated gastric disease remains a major global health problem. Previous work has indicated that the likelihood of gastric cancer development is linked to the ability of H. pylori to adapt to the host environment and deliver the CagA protein to host cells, where it alters host cell signaling. This project will specifically investigate the process of gene regulation in H. pylori as a means to understand survival in the host and to potentially identify novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI065529-06A1
Application #
8710811
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mills, Melody
Project Start
2005-07-01
Project End
2014-07-31
Budget Start
2013-08-12
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$357,220
Indirect Cost
$118,293
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817