Helicobacter pylori dupA is polymorphic, and its active form induces proinflammatory cytokine secretion by mononuclear cells

J Infect Dis. 2010 Jul 15;202(2):261-9. doi: 10.1086/653587.

Abstract

Background: Infection with Helicobacter pylori possessing a newly described virulence factor--duodenal ulcer-promoting gene A (dupA)--has been associated with duodenal ulceration and increased gastric inflammation.

Methods: The dupA locus of 34 strains was sequenced. A panel of dupA mutants was generated and cocultured with human gastric epithelial cells and peripheral blood mononuclear cells; proinflammatory cytokine release was measured. IL8 expression was measured in human gastric biopsy specimens and related to the dupA and cagA status of infecting strains.

Results: Most H. pylori strains had a dupA allele that was longer (1884 bp; dupA1) than previously described dupA alleles, although some had truncated versions (dupA2). Unlike the best-characterized H. pylori virulence determinant, the cag pathogenicity island (cag PaI), neither dupA type induced release of interleukin (IL)-8 from gastric epithelial cells. However, infections due to dupA-positive strains were associated with higher-level mucosal IL-8 messenger RNA expression in the human stomach than were infections due to dupA-negative strains. To explain this paradox, we found that dupA1 (but not dupA2 or the cag PaI) substantially increased H. pylori-induced IL-12p40 and IL-12p70 production from CD14(+) mononuclear cells. Other T helper 1-associated cytokines were also modestly induced.

Conclusion: We suggest that virulent H. pylori strains cause inflammation by stimulating epithelial cells through cag-encoded proteins and mononuclear inflammatory cells through dupA1 products.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Coculture Techniques
  • Cytokines / blood
  • Cytokines / metabolism
  • DNA Primers
  • Flow Cytometry
  • Gastric Mucosa / pathology
  • Gene Amplification
  • Helicobacter Infections / genetics*
  • Helicobacter Infections / pathology
  • Helicobacter pylori / genetics*
  • Helicobacter pylori / pathogenicity*
  • Humans
  • Interleukin-8 / deficiency
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / pathology
  • Molecular Sequence Data
  • Mutation
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Virulence Factors / genetics*

Substances

  • Cytokines
  • DNA Primers
  • DupA protein, Helicobacter pylori
  • Interleukin-8
  • Virulence Factors