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Reduced activation of inflammatory responses in host cells by mouse-adapted Helicobacter pylory isolates
Dana J Philpott1, Djilali Belaid, Pascale Troubadour
1Unité de Pathogènie Microbienne Moléculaire (INSERM U389), 28 rue du Dr Roux, Paris 75724, France.
Abstract:
Helicobacter pylori strains that harbour the Cag pathogenicity island (Cag PAI) induce interleukin (IL)-8 secretion in gastric epithelial cells, via the activation of NF- kappa B, and are associated with severe inflammation in humans. To investigate the influence of Cag PAI-mediated inflammatory responses on H. pylori adaptation to mice, a selection of H. pylori clinical isolates (n = 12) was cag PAI genotyped and tested in co-culture assays with AGS gastric epithelial cells, and in mouse colonization studies. Six isolates were shown to harbour a complete cag PAI and to induce NF- kappa B activation and IL-8 secretion in AGS cells. Of the eight isolates that spontaneously colonized mice, six had a cag PAI(-) genotype and did not induce pro-inflammatory responses in these cells. Mouse-to-mouse passage of the two cag PAI(+) -colonizing strains yielded host-adapted variants that infected mice with bacterial loads 100-fold higher than those of the respective parental strains (P= 0.001). These mouse-adapted variants were affected in their capacity to induce pro-inflammatory responses in host cells, yet no changes in cag PAI gene content were detected between the strains by DNA microarray analysis. This work provides evidence for in vivo selection of H. pylori bacteria with a reduced capacity to induce inflammatory responses and suggests that such bacteria are better adapted to colonize mice.
Insights
Helicobacter pylori strains with the Cag pathogenicity island (Cag PAI) cause inflammation. Adapted strains with reduced inflammation capacity showed enhanced mouse colonization, suggesting selection against inflammatory responses.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Helicobacter pylori strains possessing the Cag pathogenicity island (Cag PAI) trigger interleukin-8 (IL-8) secretion in gastric cells through NF-κB activation, correlating with severe human inflammation.
- The role of Cag PAI-mediated inflammation in H. pylori adaptation and colonization in vivo remains incompletely understood.
Purpose of the Study:
- To investigate how Cag PAI-mediated inflammatory responses influence H. pylori adaptation in a mouse model.
- To determine if reduced pro-inflammatory capacity enhances H. pylori colonization in mice.
Main Methods:
- Genotyping of Cag PAI in 12 H. pylori clinical isolates.
- Co-culture assays with AGS gastric epithelial cells to assess NF-κB activation and IL-8 secretion.
- Mouse colonization studies and mouse-to-mouse passage to evaluate adaptation.
Main Results:
- Six isolates with a complete Cag PAI induced NF-κB activation and IL-8 secretion in AGS cells.
- Six of eight colonizing isolates were Cag PAI-negative and did not induce pro-inflammatory responses.
- Two Cag PAI-positive colonizing strains, upon mouse passage, evolved into host-adapted variants with 100-fold higher bacterial loads.
- These adapted variants exhibited reduced pro-inflammatory responses without detectable changes in Cag PAI gene content.
Conclusions:
- H. pylori undergoes in vivo selection for variants with a diminished capacity to induce inflammatory responses.
- Reduced induction of inflammation is associated with improved H. pylori adaptation and colonization in the mouse model.