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Upon delivery into gastric epithelial cells via type IV secretion, the <jats:italic>cagA<\/jats:italic>-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 <jats:italic>H<\/jats:italic>. <jats:italic>pylori<\/jats:italic> strain (Hp_TH2099) naturally infecting the stomach of a housed macaque, indicating a zoonotic feature of <jats:italic>H<\/jats:italic>. <jats:italic>pylori<\/jats:italic> 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\u2009+\u20095 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 <jats:italic>H<\/jats:italic>. <jats:italic>pylori<\/jats:italic> standard strain, infection of mouse ES cell-derived gastric organoids with Hp_TH2099 failed to elicit CagA-dependent epithelial destruction. Thus, the macaque-isolated <jats:italic>H<\/jats:italic>. <jats:italic>pylori<\/jats:italic> showed low virulence due to attenuated CagA activity through multiple substitutions in the sequences involved in binding with SHP2 and PAR1b.<\/jats:p>","DOI":"10.1038\/s41598-018-34425-4","type":"journal-article","created":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T19:39:34Z","timestamp":1540323574000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate"],"prefix":"10.1038","volume":"8","author":[{"given":"Kana","family":"Hashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Imai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4289-1115","authenticated-orcid":false,"given":"Koji","family":"Yahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamrunnesa","family":"Tahmina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Azuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Miyabe-Nishiwaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachi","family":"Niimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munehiro","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Hatakeyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,29]]},"reference":[{"key":"34425_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0002-9343(96)00273-2","volume":"102","author":"RM Peek Jr.","year":"1997","unstructured":"Peek, R. 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