Analysis of the H. Pylori cag pathogenicity island

Summary

Principal Investigator: TIMOTHY COVER
Affiliation: Vanderbilt University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Persistent colonization of the human stomach with the Gram negative bacterium Helicobacter pylori is a risk factor for the development of gastric cancer and peptic ulcer disease. The long-term goals of this work are to understand the molecular mechanisms by which H. pylori causes these diseases, and to develop effective means for the prevention and treatment of these diseases. H. pylori isolates from different humans exhibit a considerable level of genetic diversity. One chromosomal region that is present in some H. pylori strains but not others is the cag pathogenicity island (PAI), a 40 kb region that is predicted to encode 27 different proteins. 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-negative strains. The cag PAI encodes an effector protein, CagA, and multiple proteins that translocate CagA into gastric epithelial cells via a type IV secretion process. This project describes plans to investigate the molecular mechanisms by which CagA is translocated into gastric epithelial cells. The aims of the project are i) to analyze subassemblies of the cag PAI-encoded type IV secretion apparatus;ii) to investigate the subcellular localization of H. pylori Cag proteins;and iii) to analyze effects of CagA in the stomachs of animal models. These studies should lead to important advances in our understanding of the molecular mechanisms by which products of the H. pylori cag PAI contribute to the development of gastroduodenal diseases. The presence of a bacterium known as Helicobacter pylori in the human stomach contributes to the development of cancer of the stomach and peptic ulcer disease. This research seeks to understand how a bacterial infection can lead to these diseases. The long-term goals are to develop effective means for the prevention and treatment of stomach cancer and peptic ulcer disease.
Funding Period: ----------------2008 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Helicobacter pylori HopQ outer membrane protein attenuates bacterial adherence to gastric epithelial cells
    John T Loh
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    FEMS Microbiol Lett 289:53-8. 2008
  2. pmc The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay
    Christian González-Rivera
    Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 80:2578-88. 2012
  3. pmc Analysis of Helicobacter pylori cagA promoter elements required for salt-induced upregulation of CagA expression
    John T Loh
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 80:3094-106. 2012
  4. pmc Alterations in Helicobacter pylori triggered by contact with gastric epithelial cells
    Elizabeth M Johnson
    Department of Medicine, Vanderbilt University School of Medicine Nashville, TN, USA
    Front Cell Infect Microbiol 2:17. 2012
  5. pmc An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA
    Jens Conradi
    Department of Chemistry, Bielefeld University Bielefeld, Germany
    Front Cell Infect Microbiol 2:70. 2012
  6. pmc Perspectives on methodology for in vitro culture of Helicobacter pylori
    Timothy L Cover
    Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
    Methods Mol Biol 921:11-5. 2012
  7. pmc Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Clin Invest 123:479-92. 2013
  8. pmc Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes
    Stacy S Duncan
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    PLoS ONE 8:e55120. 2013
  9. pmc Functional plasticity in the type IV secretion system of Helicobacter pylori
    Roberto M Barrozo
    Center for Comparative Medicine, University of California Davis, Davis, California, United States of America
    PLoS Pathog 9:e1003189. 2013
  10. pmc High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis
    Jennifer A Gaddy
    Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 81:2258-67. 2013

Scientific Experts

  • TIMOTHY COVER
  • Keith Wilson
  • MARK MCCLAIN
  • Holly M Scott Algood
  • John T Loh
  • Richard M Peek
  • Jennifer A Gaddy
  • Carrie L Shaffer
  • Pelayo Correa
  • Jana N Radin
  • Luis E Bravo
  • M Blanca Piazuelo
  • Stacy S Duncan
  • Judith Romero-Gallo
  • Liviu A Sicinschi
  • Christian González-Rivera
  • Elizabeth M Johnson
  • Barbara G Schneider
  • Thibaut de Sablet
  • Seth R Bordenstein
  • David B Friedman
  • Bradley J Voss
  • Nuri Kodaman
  • Giovanni Suarez
  • Jennifer M Noto
  • Roberto M Barrozo
  • Pieter L Valk
  • W Hayes McDonald
  • Jens Conradi
  • Dawn A Israel
  • Toni A Nagy
  • M Kay Washington
  • Kelly A Gangwer
  • Rupesh Chaturvedi
  • Fang Yan
  • Reed H Harder
  • Rafal S Sobota
  • Robertino Mera
  • Alvaro Pazos
  • Scott M Williams
  • Feng Zhang
  • Douglas R Morgan
  • Taryn A Cariaga
  • Daniel C Colvin
  • Cara L Cooke
  • Josephine Y Lee
  • Shumin Tan
  • Lori M Hansen
  • James C Slaughter
  • Jason A Metcalf
  • Manuel R Amieva
  • Anna M Lam
  • Jay V Solnick
  • John Loh
  • Dexter T Thompson
  • Marco Wissbrock
  • Carmela Michalek
  • Nicole Tegtmeyer
  • Corinna Gagell
  • Norbert Sewald
  • Benjamin D Gold
  • Ronald Frank
  • Maria C Yepez
  • Steffen Backert
  • Marta Woźna
  • Alberto G Delgado
  • Lydia E Wroblewski
  • Seth R Ogden
  • Alberto Delgado
  • Susan E Ivie
  • Ewa E Hennig
  • Robertino M Mera
  • Mohammad Asim
  • Salisha Hill
  • Dingzhi Wang
  • Jennifer Noto
  • Sebastian Suerbaum
  • Andrzej M Krezel
  • Shobhana S Gupta
  • D Borden Lacy
  • Stuart S Hobbs
  • Hanwei Cao
  • Peter J Dempsey
  • D Brent Polk
  • Uma Krishna
  • Victor J Torres

Detail Information

Publications28

  1. pmc Helicobacter pylori HopQ outer membrane protein attenuates bacterial adherence to gastric epithelial cells
    John T Loh
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    FEMS Microbiol Lett 289:53-8. 2008
    ..These data indicate that in some strains of H. pylori, the HopQ protein can attenuate bacterial adherence to gastric epithelial cells...
  2. pmc The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay
    Christian González-Rivera
    Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 80:2578-88. 2012
    ..Correspondingly, i2 forms of VacA bound to Jurkat cells less avidly than did i1 forms of VacA. These results indicate that the VacA i-region is an important determinant of VacA effects on human T cell function...
  3. pmc Analysis of Helicobacter pylori cagA promoter elements required for salt-induced upregulation of CagA expression
    John T Loh
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 80:3094-106. 2012
    ..In summary, there is considerable heterogeneity among H. pylori strains in salt-regulated CagA expression, and these differences are attributable to variation in a specific DNA motif upstream of the cagA transcriptional start site...
  4. pmc Alterations in Helicobacter pylori triggered by contact with gastric epithelial cells
    Elizabeth M Johnson
    Department of Medicine, Vanderbilt University School of Medicine Nashville, TN, USA
    Front Cell Infect Microbiol 2:17. 2012
    ..pylori, and upon entry into this niche, the bacteria alter their behavior in a manner that optimizes bacterial proliferation and persistent colonization of the host...
  5. pmc An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA
    Jens Conradi
    Department of Chemistry, Bielefeld University Bielefeld, Germany
    Front Cell Infect Microbiol 2:70. 2012
    ..pylori pathogenesis...
  6. pmc Perspectives on methodology for in vitro culture of Helicobacter pylori
    Timothy L Cover
    Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
    Methods Mol Biol 921:11-5. 2012
    ..Analysis of H. pylori growth in chemically defined media has provided insight into the nutritional requirements, physiology, and metabolic capacities of this organism...
  7. pmc Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Clin Invest 123:479-92. 2013
    ..These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer...
  8. pmc Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes
    Stacy S Duncan
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    PLoS ONE 8:e55120. 2013
    ..pylori strains. Moreover, these divergent genes represent robust biomarkers that can be used to differentiate East Asian and non-Asian H. pylori strains...
  9. pmc Functional plasticity in the type IV secretion system of Helicobacter pylori
    Roberto M Barrozo
    Center for Comparative Medicine, University of California Davis, Davis, California, United States of America
    PLoS Pathog 9:e1003189. 2013
    ..pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and "tunes" the host inflammatory response so as to maximize persistent infection...
  10. pmc High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis
    Jennifer A Gaddy
    Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 81:2258-67. 2013
    ..Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains...
  11. pmc Flagellar localization of a Helicobacter pylori autotransporter protein
    Jana N Radin
    Department of Medicine, Vanderbilt University, School of Medicine, Nashville, Tennessee, USA
    MBio 4:e00613-12. 2013
    ..The flagellar localization of FaaA differs markedly from the localization of other known autotransporters, and the current results reveal an important role of FaaA in flagellar localization and motility...
  12. pmc Control of gene expression in Helicobacter pylori using the Tet repressor
    Mark S McClain
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA Electronic address
    J Microbiol Methods 95:336-41. 2013
    ..These studies demonstrate the effectiveness of the tetR-tetO system to control gene expression in H. pylori and provide an improved system for studying H. pylori physiology and pathogenesis. ..
  13. pmc Human and Helicobacter pylori coevolution shapes the risk of gastric disease
    Nuri Kodaman
    Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Divisions of Gastroenterology and Infectious Diseases, Department of Medicine, and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
    Proc Natl Acad Sci U S A 111:1455-60. 2014
    ..Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population. ..
  14. pmc Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori
    Bradley J Voss
    Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    J Bacteriol 196:2455-71. 2014
    ..Collectively, these results provide new insights into the repertoire of surface-exposed H. pylori proteins that may mediate bacterium-host interactions, as well as the cell surface topology of these proteins. ..
  15. pmc Non-invasive genotyping of Helicobacter pylori cagA, vacA, and hopQ from asymptomatic children
    Liviu A Sicinschi
    Division of Gastroenterology, Dept of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    Helicobacter 17:96-106. 2012
    ..Our aim is to genotype cagA, hopQ, and vacA alleles in stool DNA samples of healthy Colombian children residing in an area with high incidence of gastric cancer, to avoid selection bias resulting from endoscopy...
  16. pmc Genome sequence analysis of Helicobacter pylori strains associated with gastric ulceration and gastric cancer
    Mark S McClain
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 2605, USA
    BMC Genomics 10:3. 2009
    ..In this study, we analyzed the genome sequences of an H. pylori strain (98-10) isolated from a patient with gastric cancer and an H. pylori strain (B128) isolated from a patient with gastric ulcer disease...
  17. pmc Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis
    Fang Yan
    Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0696, USA
    Gastroenterology 136:1297-1307, e1-3. 2009
    ..Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival...
  18. pmc Helicobacter pylori in health and disease
    Timothy L Cover
    Department of Medicine, Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37232, USA
    Gastroenterology 136:1863-73. 2009
    ....
  19. pmc Regulation of gastric B cell recruitment is dependent on IL-17 receptor A signaling in a model of chronic bacterial infection
    Holly M Scott Algood
    Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA
    J Immunol 183:5837-46. 2009
    ..In contrast to many chronic inflammatory diseases in which IL-17RA signaling promotes an inflammatory response, IL-17RA signaling down-regulates the chronic mononuclear inflammation elicited by H. pylori infection...
  20. pmc Analysis of protein expression regulated by the Helicobacter pylori ArsRS two-component signal transduction system
    John T Loh
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    J Bacteriol 192:2034-43. 2010
    ..These results provide further definition of the ArsRS regulon and underscore the importance of the ArsRS system in regulating expression of H. pylori proteins during bacterial growth at both neutral pH and acidic pH...
  21. pmc Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA
    Kelly A Gangwer
    Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    J Bacteriol 192:6126-35. 2010
    ..Taken together, these results indicate that positive selection has shaped the phylogenetic structure of VacA and CagA, and each of these virulence determinants has evolved separately from the core genome...
  22. pmc Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk
    Thibaut de Sablet
    Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, MRBIV, Room 1030C, 2215 Garland Avenue, Nashville, TN 37232, USA
    Gut 60:1189-95. 2011
    ..Our aim was to investigate the ancestral origin of H pylori strains isolated from subjects in these high- and low-risk regions and to determine whether this is a predictive determinant of precancerous lesions...
  23. pmc Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells
    Jana N Radin
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 2605, USA
    Infect Immun 79:2535-43. 2011
    ....
  24. pmc β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia
    Toni A Nagy
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
    Gastroenterology 141:553-64. 2011
    ..We used a carcinogenic H pylori strain to define the role of microbial virulence constituents and PPARδ in regulating epithelial responses that mediate development of adenocarcinoma...
  25. pmc Analysis of cagA in Helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity
    John T Loh
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    Cancer Epidemiol Biomarkers Prev 20:2237-49. 2011
    ..Helicobacter pylori infection is a risk factor for the development of gastric cancer, and the bacterial oncoprotein CagA contributes to gastric carcinogenesis...
  26. pmc Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface
    Carrie L Shaffer
    Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS Pathog 7:e1002237. 2011
    ..In summary, these results indicate that CagH, CagI, and CagL are components of a T4SS subassembly involved in pilus biogenesis, and highlight the important role played by unique constituents of the H. pylori cag T4SS...
  27. pmc J-Western forms of Helicobacter pylori cagA constitute a distinct phylogenetic group with a widespread geographic distribution
    Stacy S Duncan
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    J Bacteriol 194:1593-604. 2012
    ..pylori...