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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<jats:sup> \u2212<\/jats:sup> mutant, which fails to assemble a T4SS, were used to infect wild-type or Tlr9<jats:sup> \u2212\/\u2212<\/jats:sup> C57BL\/6 mice. PMSS1-infected Tlr9<jats:sup> \u2212\/\u2212<\/jats:sup> 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<jats:sup> \u2212<\/jats:sup> mutant only developed minimal inflammation. Tlr9<jats:sup> \u2212\/\u2212<\/jats:sup> 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 T<jats:sub>H<\/jats:sub>1 or T<jats:sub>H<\/jats:sub>2 cytokines in infected mice when stratified by host genotype. However, gastric mucosal levels of IL-17 were significantly increased in infected Tlr9<jats:sup> \u2212\/\u2212<\/jats:sup> mice compared with infected wild-type mice, and H. pylori infection of IL-17A<jats:sup> \u2212\/\u2212<\/jats:sup> 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. <\/jats:p>","DOI":"10.1152\/ajpgi.00175.2016","type":"journal-article","created":{"date-parts":[[2016,10,7]],"date-time":"2016-10-07T02:59:18Z","timestamp":1475809158000},"page":"G852-G858","source":"Crossref","is-referenced-by-count":43,"title":["TLR9 activation suppresses inflammation in response to <i>Helicobacter pylori<\/i> infection"],"prefix":"10.1152","volume":"311","author":[{"given":"Matthew G.","family":"Varga","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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