Persistent Helicobacter pylori colonization results in diseases such as gastritis, ulcer disease, gastric carcinoma, and iron deficiency anemia (IDA). Given the large environmental fluctuations that H. pylori experiences in the stomach, the bacterium must be adept at regulating gene expression as a means to adapt and survive in this niche. Furthermore, H. pylori utilizes environmental signals as a means to control gene expression. For example, the bacterium utilizes iron availability as signal to regulate expression of colonization and virulence genes. On the regulatory front, the Ferric Uptake Regulator (Fur) is known to function as an iron co-factored regulatory protein. 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. Our preliminary 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 to examine expression and delivery of CagA in vivo. We predict that our work will shed significant insight into the process by which expression of this key virulence factor is mediated in H. pylori and help to determine the role of environmental signaling in infection and ultimate disease development. These studies will fill a fundamental gap in our knowledge and could 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
Exploratory/Developmental Grants (R21)
Project #
1R21AI109405-01
Application #
8620262
Study Section
Special Emphasis Panel (ZRG1-IDM-B (80))
Program Officer
Mills, Melody
Project Start
2014-08-15
Project End
2016-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$224,271
Indirect Cost
$74,271
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817