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dc.contributor.authorHashi, Kana
dc.contributor.authorImai, Chihiro
dc.contributor.authorYahara, Koji
dc.contributor.authorTahmina, Kamrunnesa
dc.contributor.authorHayashi, Takeru
dc.contributor.authorAzuma, Takeshi
dc.contributor.authorMiyabe-Nishiwaki, Takako
dc.contributor.authorSato, Hideyuki
dc.contributor.authorMatsuoka, Masao
dc.contributor.authorNiimi, Sachi
dc.contributor.authorOkamoto, Munehiro
dc.contributor.authorHatakeyama, Masanori
dc.contributor.alternative矢原, 耕史
dc.contributor.alternative林, 剛瑠
dc.contributor.alternative東, 健
dc.contributor.alternative宮部, 貴子
dc.contributor.alternative松岡, 雅雄
dc.contributor.alternative新美, 幸
dc.contributor.alternative岡本, 宗裕
dc.contributor.alternative畠山, 昌則
dc.date.accessioned2018-11-22T00:46:13Z-
dc.date.available2018-11-22T00:46:13Z-
dc.date.issued2018-10-29
dc.identifier.issn2045-2322
dc.identifier.urihttp://hdl.handle.net/2433/235254-
dc.description.abstractHelicobacter pylori cagA-positive strains are critically involved in the development of gastric cancer. Upon delivery into gastric epithelial cells via type IV secretion, the cagA-encoded CagA interacts with and thereby perturbs the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1b via the tyrosine-phosphorylated EPIYA-C/D segment and the CM sequence, respectively. Importantly, sequences spanning these binding regions exhibit variations among CagA proteins, which influence the pathobiological/oncogenic potential of individual CagA. Here we isolated an H. pylori strain (Hp_TH2099) naturally infecting the stomach of a housed macaque, indicating a zoonotic feature of H. pylori infection. Whole genome sequence analysis revealed that Hp_TH2099 belongs to the hpAsia2 cluster and possesses ABC-type Western CagA, which contains hitherto unreported variations in both EPIYA-C and CM sequences. The CM variations almost totally abolished PAR1b binding. Whereas pTyr + 5 variation in the EPIYA-C segment potentiated SHP2-binding affinity, pTyr-2 variation dampened CagA tyrosine phosphorylation and thus impeded CagA-SHP2 complex formation. As opposed to the H. pylori standard strain, infection of mouse ES cell-derived gastric organoids with Hp_TH2099 failed to elicit CagA-dependent epithelial destruction. Thus, the macaque-isolated H. pylori showed low virulence due to attenuated CagA activity through multiple substitutions in the sequences involved in binding with SHP2 and PAR1b.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherSpringer Nature America, Inc
dc.rights© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.subjectBacterial host response
dc.subjectBacterial pathogenesis
dc.subjectBacterial toxins
dc.subjectCellular microbiology
dc.subjectPathogens
dc.titleEvaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
dc.type.niitypeJournal Article
dc.identifier.jtitleScientific Reports
dc.identifier.volume8
dc.identifier.spage15981
dc.relation.doi10.1038/s41598-018-34425-4
dc.textversionpublisher
dc.identifier.pmid30374120
dc.identifier.kaken16H06373 / 16K15273 / 15J05771
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