title: Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system.
abstract: Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Varga
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Shaffer
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Sierra
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: G
authors.initials: G
authors.lastname: Suarez
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Whitaker
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: U S
authors.initials: US
authors.lastname: Krishna
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Delgado
authors.affiliation: Department of Internal Medicine, Unit of Gastroenterology, National University of Colombia School of Medicine, Bogota, Colombia.
authors.forename: M A
authors.initials: MA
authors.lastname: Gomez
authors.affiliation: Department of Chemistry, Umeå University, Umeå, Sweden.|Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden.
authors.forename: J A D
authors.initials: JA
authors.lastname: Good
authors.affiliation: Department of Chemistry, Umeå University, Umeå, Sweden.|Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Almqvist
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Correa
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hadjifrangiskou
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Peek
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D063646:Carcinogenesis; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D009154:Mutation; D013274:Stomach Neoplasms / Q000209:etiology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D000069319:Type IV Secretion Systems
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D051217:Toll-Like Receptor 9; D000069319:Type IV Secretion Systems