title: TLR9 activation suppresses inflammation in response to Helicobacter pylori infection.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Varga
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Delgado
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Suarez
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Whitaker
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Uma S
authors.initials: US
authors.lastname: Krishna
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Rachna V
authors.initials: RV
authors.lastname: Patel
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Holly M S
authors.initials: HM
authors.lastname: Algood
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; richard.peek@vanderbilt.edu.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
mesh_terms: D000818:Animals; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori; D007249:Inflammation / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D051217:Toll-Like Receptor 9
keywords: Helicobacter pylori; Toll-like receptor 9; gastritis