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


CONCLUSIONS
We suggest that virulent H. pylori strains cause inflammation by stimulating epithelial cells through cag-encoded proteins and mononuclear inflammatory cells through dupA1 products.
Nottingham Digestive Diseases Centre Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
Nawfal R
NR
Hussein
Richard H
RH
Argent
Christian K
CK
Marx
Sapna R
SR
Patel
Karen
K
Robinson
John C
JC
Atherton
D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D017931:DNA Primers; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000473:pathology; D005784:Gene Amplification; D016481:Helicobacter Infections / Q000235:genetics* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D016209:Interleukin-8 / Q000172:deficiency / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D037521:Virulence Factors / Q000235:genetics*
D016207:Cytokines; D017931:DNA Primers; C528428:DupA protein, Helicobacter pylori; D016209:Interleukin-8; D037521:Virulence Factors