) Helicobacter pylori is a Gram-negative bacterium that colonizes the gastric mucosa of humans. Although most H. pylori-infected persons remain asymptomatic, potentially serious sequelae of infection include gastric adenocarcinoma, duodenal or gastric ulceration, and gastric lymphoma. Gastric cancer is the third leading cause of cancer-related death worldwide, and H. pylori has been classified as a type I carcinogen by the World Health Organization. One of the major secreted proteins of H. pylori is a toxin known as VacA. There is a high level of genetic variation among vacA alleles from unrelated H. pylori strains, and the encoded VacA proteins exhibit marked differences in their ability to cause alterations in human cells. A large body of literature indicates that H. pylori strains containing certain forms of vacA (termed s1, i1, or m1) are associated with a higher risk of gastric cancer or peptic ulcer disease than are strains containing other forms of vacA (termed s2, i2, or m2). Thus, VacA is considered to be an important H. pylori virulence factor. Most cellular effects of VacA are dependent on its ability to oligomerize and form anion-selective membrane channels, but relatively little is known about the molecular basis for these two critical steps in the VacA mechanism of action, and almost nothing is known about the roles of VacA oligomerization and pore formation in vivo. Therefore, the specific aims are to (i) elucidate the process by which VacA assembles into oligomeric structures; (ii) elucidate the process by which VacA inserts into membranes to form anion-selective channels, and (iii) define the consequences of VacA oligomerization and membrane channel formation in animal models. This work is relevant not only for the study of H. pylori-associated diseases, but will also increase our understanding of bacterial pore-forming toxins, chloride-conducting membrane channels, and ?-helical passenger domains secreted by an autotransporter pathway.

Public Health Relevance

(Relevance to Public Health) A bacterium known as Helicobacter pylori colonizes the stomach in about half of all humans; most do not develop any symptoms related to this infection, but some develop stomach cancer or peptic ulcer disease. Stomach cancer is the third leading cause of cancer-related death worldwide and H. pylori infection is the leading cause of stomach cancer. The long-term goals of this research are to understand the molecular mechanisms by which H. pylori infection can lead to disease, and to understand the basis for variation in clinical outcomes among H. pylori- infected persons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039657-22
Application #
9616842
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mills, Melody
Project Start
1996-05-01
Project End
2022-08-31
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
22
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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