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 second 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 most important virulence factors of H. pylori is a protein known as CagA. CagA is secreted through a type IV secretion system (T4SS) and enters gastric epithelial cells, where it causes a complex set of alterations in cellular signaling that are associated with malignant transformation. CagA and components of the T4SS are encoded by genes within a chromosomal region known as the cag pathogenicity island (PAI), which is present in some H. pylori strains but not others. The incidence of symptomatic gastroduodenal disease (gastric cancer or peptic ulceration) is higher among persons infected with cag PAI-positive strains than among persons infected with cag PAI-negative strains. The effects of CagA on host cells have been studied in great detail, but thus far there has been only limited study of CagA secretion. The T4SS used for CagA secretion exhibits unique and specialized features that differ from those of well-studied T4SSs used for mobilization of DNA. The overarching long-term goals of this research are to develop a better understanding of the molecular mechanisms by which H. pylori causes gastric disease, and to determine why gastric disease arises in a small subset of infected persons while most remain asymptomatic or derive health benefits.
The aims of the project are i) To define the molecular organization of the membrane-spanning cag T4SS core complex; ii) To determine the three-dimensional structure of the cag T4SS core complex; and (iii) To define consequences of T4SS activity in animal models of H. pylori infection and gastric malignancy. Methods will include robust electron microscopy approaches for analyzing the structure of the T4SS core complex, specialized techniques for genetic manipulation in H. pylori, and newly developed methods for regulating the transcription of genes encoding T4SS components. These studies should provide important advances in our understanding of the molecular mechanisms by which H. pylori infection can lead to gastric cancer and other gastric diseases. On a broader scope, these studies will increase our understanding of bacterial secretion systems and the delivery of virulence factors into host cells, as well as molecular mechanisms underlying microbe-induced carcinogenesis.

Public Health Relevance

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 #
3R01AI118932-03S2
Application #
9428227
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mills, Melody
Project Start
2016-02-18
Project End
2021-01-31
Budget Start
2017-07-27
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Raghunathan, Krishnan; Foegeding, Nora J; Campbell, Anne M et al. (2018) Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. Infect Immun 86:
Beckett, Amber C; Loh, John T; Chopra, Abha et al. (2018) Helicobacter pylori genetic diversification in the Mongolian gerbil model. PeerJ 6:e4803
Loh, John T; Beckett, Amber C; Scholz, Matthew B et al. (2018) High-Salt Conditions Alter Transcription of Helicobacter pylori Genes Encoding Outer Membrane Proteins. Infect Immun 86:
Noto, Jennifer M; Chopra, Abha; Loh, John T et al. (2018) Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 67:1793-1804
Butt, Julia; Blot, William J; Teras, Lauren R et al. (2018) Antibody Responses to Streptococcus Gallolyticus Subspecies Gallolyticus Proteins in a Large Prospective Colorectal Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 27:1186-1194
McClain, Mark S; Beckett, Amber C; Cover, Timothy L (2017) Helicobacter pylori Vacuolating Toxin and Gastric Cancer. Toxins (Basel) 9:
Bullock, Kennady K; Shaffer, Carrie L; Brooks, Andrew W et al. (2017) Genetic signatures for Helicobacter pylori strains of West African origin. PLoS One 12:e0188804
González-Rivera, Christian; Campbell, Anne M; Rutherford, Stacey A et al. (2016) A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain. Infect Immun 84:2662-70
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
Pyburn, Tasia M; Foegeding, Nora J; González-Rivera, Christian et al. (2016) Structural organization of membrane-inserted hexamers formed by Helicobacter pylori VacA toxin. Mol Microbiol 102:22-36

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