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Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system
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2016 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 48, 6262-6269 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016. Vol. 35, no 48, 6262-6269 p.
National Category
Chemical Sciences Microbiology in the medical area Cancer and Oncology Medical Genetics
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URN: urn:nbn:se:umu:diva-128864DOI: 10.1038/onc.2016.158ISI: 000388857700010OAI: oai:DiVA.org:umu-128864DiVA: diva2:1057229
Note

Supplementary information available for this article at http://www.nature.com/onc/journal/v35/n48/suppinfo/onc2016158s1.html

Available from: 2016-12-16 Created: 2016-12-16 Last updated: 2017-01-13Bibliographically approved

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Good, James A DAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)
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CiteExportLink to record
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