Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate

Abstract Helicobacter 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...

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Autores principales:	Kana Hashi, Chihiro Imai, Koji Yahara, Kamrunnesa Tahmina, Takeru Hayashi, Takeshi Azuma, Takako Miyabe-Nishiwaki, Hideyuki Sato, Masao Matsuoka, Sachi Niimi, Munehiro Okamoto, Masanori Hatakeyama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Pylori cagA-positive Strains Western CagA Organoid CagA Protein East Asian CagA Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f8666df3919444ac8c305271f76849db
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spelling	oai:doaj.org-article:f8666df3919444ac8c305271f76849db2021-12-02T15:07:58ZEvaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate10.1038/s41598-018-34425-42045-2322https://doaj.org/article/f8666df3919444ac8c305271f76849db2018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34425-4https://doaj.org/toc/2045-2322Abstract Helicobacter 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.Kana HashiChihiro ImaiKoji YaharaKamrunnesa TahminaTakeru HayashiTakeshi AzumaTakako Miyabe-NishiwakiHideyuki SatoMasao MatsuokaSachi NiimiMunehiro OkamotoMasanori HatakeyamaNature PortfolioarticlePylori cagA-positive StrainsWestern CagAOrganoidCagA ProteinEast Asian CagAMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pylori cagA-positive Strains Western CagA Organoid CagA Protein East Asian CagA Medicine R Science Q
spellingShingle	Pylori cagA-positive Strains Western CagA Organoid CagA Protein East Asian CagA Medicine R Science Q Kana Hashi Chihiro Imai Koji Yahara Kamrunnesa Tahmina Takeru Hayashi Takeshi Azuma Takako Miyabe-Nishiwaki Hideyuki Sato Masao Matsuoka Sachi Niimi Munehiro Okamoto Masanori Hatakeyama Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
description	Abstract Helicobacter 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.
format	article
author	Kana Hashi Chihiro Imai Koji Yahara Kamrunnesa Tahmina Takeru Hayashi Takeshi Azuma Takako Miyabe-Nishiwaki Hideyuki Sato Masao Matsuoka Sachi Niimi Munehiro Okamoto Masanori Hatakeyama
author_facet	Kana Hashi Chihiro Imai Koji Yahara Kamrunnesa Tahmina Takeru Hayashi Takeshi Azuma Takako Miyabe-Nishiwaki Hideyuki Sato Masao Matsuoka Sachi Niimi Munehiro Okamoto Masanori Hatakeyama
author_sort	Kana Hashi
title	Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
title_short	Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
title_full	Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
title_fullStr	Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
title_full_unstemmed	Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate
title_sort	evaluating the origin and virulence of a helicobacter pylori caga-positive strain isolated from a non-human primate
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/f8666df3919444ac8c305271f76849db
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Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate

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