TLR9 activation suppresses inflammation in response to Helicobacter pylori infection

Am J Physiol Gastrointest Liver Physiol. 2016 Nov 1;311(5):G852-G858. doi: 10.1152/ajpgi.00175.2016. Epub 2016 Oct 6.


Helicobacter pylori (H. pylori) induces chronic gastritis in humans, and infection can persist for decades. One H. pylori strain-specific constituent that augments disease risk is the cag pathogenicity island. The cag island encodes a type IV secretion system (T4SS) that translocates DNA into host cells. Toll-like receptor 9 (TLR9) is an innate immune receptor that detects hypo-methylated CpG DNA motifs. In this study, we sought to define the role of the H. pylori cag T4SS on TLR9-mediated responses in vivo. H. pylori strain PMSS1 or its cagE- mutant, which fails to assemble a T4SS, were used to infect wild-type or Tlr9-/- C57BL/6 mice. PMSS1-infected Tlr9-/- mice developed significantly higher levels of inflammation, despite similar levels of colonization density, compared with PMSS1-infected wild-type mice. These changes were cag dependent, as both mouse genotypes infected with the cagE- mutant only developed minimal inflammation. Tlr9-/- genotypes did not alter the microbial phenotypes of in vivo-adapted H. pylori strains; therefore, we examined host immunological responses. There were no differences in levels of TH1 or TH2 cytokines in infected mice when stratified by host genotype. However, gastric mucosal levels of IL-17 were significantly increased in infected Tlr9-/- mice compared with infected wild-type mice, and H. pylori infection of IL-17A-/- mice concordantly led to significantly decreased levels of gastritis. Thus loss of Tlr9 selectively augments the intensity of IL-17-driven immune responses to H. pylori in a cag T4SS-dependent manner. These results suggest that H. pylori utilizes the cag T4SS to manipulate the intensity of the host immune response.

Keywords: Helicobacter pylori; Toll-like receptor 9; gastritis.

MeSH terms

  • Animals
  • Gastric Mucosa / metabolism
  • Helicobacter Infections / metabolism*
  • Helicobacter pylori
  • Inflammation / metabolism*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Knockout
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / metabolism*


  • Interleukin-17
  • Toll-Like Receptor 9