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Pathogenic H elicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system

Oncogene volume 35, pages 6262–6269 (2016)Cite this article

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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.

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Acknowledgements

We acknowledge the following core laboratories and personnel at Vanderbilt University for their contributions to these studies: Tissue Acquisition and Pathology Core; Division of Animal Care; Cell Imaging Shared Resource Core (CISR) and the Digestive Disease Research Center. This work was supported by NIH R01-DK58587, R01-CA77955, P01-CA116087 and P30-DK058404 (RMP); Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH (VICTR award VR7227), APS 1-04-520-9211 and institutional funds (MH); R01-DK053620, R01-CA190612, and a Department of Veterans Affairs Merit Review grant I01BX001453 (KTW); and P01-CA028842 (KTW and PC).

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    M G Varga, K T Wilson & R M Peek

  2. Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA

    C L Shaffer, E P Skaar, K T Wilson, M Hadjifrangiskou & R M Peek

  3. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN, USA

    J C Sierra, G Suarez, M B Piazuelo, M E Whitaker, J Romero-Gallo, U S Krishna, A Delgado, P Correa, K T Wilson & R M Peek

  4. Department of Internal Medicine, Unit of Gastroenterology, National University of Colombia School of Medicine, Bogota, Colombia

    M A Gomez

  5. Department of Chemistry, Umeå University, Umeå, Sweden

    J A D Good & F Almqvist

  6. Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden

    J A D Good & F Almqvist

  7. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    E P Skaar & K T Wilson

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Varga, M., Shaffer, C., Sierra, J. et al. Pathogenic H elicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene 35, 6262–6269 (2016). https://doi.org/10.1038/onc.2016.158

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