TheHelicobacter pyloriplasticity region locusjhp0947–jhp0949is associated with duodenal ulcer disease and interleukin-12 production in monocyte cells

Abstract

Colonization with Helicobacter pylori always results in chronic gastritis, which is controlled by infiltration of mononuclear cells and the subsequent release of cytokines like interleukin (IL)-12. To identify H. pylori factors involved in inducing cytokine production in mononuclear cells, a random H. pylori mutant library was screened for the inability to induce IL-12 production in monocyte THP-1 cells. Of the 231 random mutants screened, one mutant (M1) showed a consistent twofold decrease in the amount of IL-12 induction compared to the parental strain 1061 (P <0.01). Further characterization of mutant M1 revealed that the kanamycin resistance cassette had integrated in the jhp0945 gene, which is situated in an H. pylori strain-specific plasticity region. Three reference strains possessing this plasticity region induced significantly higher amounts of IL-12 when compared to the H. pylori 26695 reference strain, which does not possess this plasticity region. The role in disease outcome of jhp0945 as well as the neighbouring plasticity region genes jhp0947 and jhp049 was assessed in a Dutch population cohort. Firstly, the presence of jhp0947 was completely linked with that of jhp0949 and was roughly associated with jhp0945 (P=0.072), but not with the cag pathogenicity island (PAI) (P=0.464). The presence of the jhp0947 and jhp0949 genes, but not of jhp0945, was significantly associated with duodenal ulcer disease when compared to gastritis (P=0.027). Therefore, the jhp0947-jhp0949 locus may be a novel putative H. pylori marker for disease outcome independent of the cag PAI.

Differences in Genome Content among Helicobacter pylori Isolates from Patients with Gastritis, Duodenal Ulcer, or Gastric Cancer Reveal Novel Disease-Associated Genes

“…Interestingly, JHP0950 has been suggested as a marker for H. pylori strains from patients with gastric extranodal marginal-zone-B-cell lymphoma of the MALT type (29). Other genes in PZ2 and previously reported as associated with DU, i.e., JHP0947 and JHP0949 (12), are in the vicinity of two genes, JHP0950 and JHP0951, found by us to be associated with DU. In fact, it was recently suggested that JHP0950 may form part of an operon that includes the JHP0949 gene (37,55).…”

“…Other studies have reported that genes located in the PZs, such as jhp0947 and jhp0949, are associated with disease (12,37,47). The dupA gene was associated with an increased risk for duodenal ulcer (DU) and a low risk for gastric atrophy and cancer (31).…”

Pathogenesis ofHelicobacter pyloriInfection

“…The latter usually have an aberrant GϩC content and often carry genes involved in virulence. A striking example of this in H. pylori is the cag PAI, but other plasticity regions have also been suggested to play a role in the pathogenesis of H. pylori infection (115,357,462,545).…”

Emerging role of IL-23/IL-17 axis inH pylori-associated pathology

“…IL-12-deficient mice have also reduced gastric inflammatory infiltration and are unable to clear H pylori infection [46] . Several virulence factors are reported to promote Th1 responses, including the plasticity region locus jhp0947-jhp0949 which is associated with duodenal ulcer disease [47] and the H pylori-NAP [29] . The Th1/Th2 balance is also influenced by phase-variable expression of Lewis bloodgroup antigens and genomic DNA recombination [48,49] .…”