Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis

ABSTRACT The Helicobacter pylori Cag type IV secretion system (T4SS) translocates the effector protein CagA and nonprotein bacterial constituents into host cells. In this study, we infected Mongolian gerbils with an H. pylori strain in which expression of the cagUT operon (required for Cag T4SS acti...

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Autores principales:	Aung Soe Lin, Mark S. McClain, Amber C. Beckett, Rhonda R. Caston, M. Lorena Harvey, Beverly R. E. A. Dixon, Anne M. Campbell, Jennifer H. B. Shuman, Neha Sawhney, Alberto G. Delgado, John T. Loh, M. Blanca Piazuelo, Holly M. Scott Algood, Timothy L. Cover
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Helicobacter pylori type IV secretion system gastric cancer carcinogenesis animal model hit-and-run hypothesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3791960f61674d22a55ee21aa1db0972
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spelling	oai:doaj.org-article:3791960f61674d22a55ee21aa1db09722021-11-15T15:56:46ZTemporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis10.1128/mBio.01296-202150-7511https://doaj.org/article/3791960f61674d22a55ee21aa1db09722020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01296-20https://doaj.org/toc/2150-7511ABSTRACT The Helicobacter pylori Cag type IV secretion system (T4SS) translocates the effector protein CagA and nonprotein bacterial constituents into host cells. In this study, we infected Mongolian gerbils with an H. pylori strain in which expression of the cagUT operon (required for Cag T4SS activity) is controlled by a TetR/tetO system. Transcript levels of cagU were significantly higher in gastric tissue from H. pylori-infected animals receiving doxycycline-containing chow (to derepress Cag T4SS activity) than in tissue from infected control animals receiving drug-free chow. At 3 months postinfection, infected animals receiving doxycycline had significantly increased gastric inflammation compared to infected control animals. Dysplasia (a premalignant histologic lesion) and/or invasive gastric adenocarcinoma were detected only in infected gerbils receiving doxycycline, not in infected control animals. We then conducted experiments in which Cag T4SS activity was derepressed during defined stages of infection. Continuous Cag T4SS activity throughout a 3-month time period resulted in higher rates of dysplasia and/or gastric cancer than observed when Cag T4SS activity was limited to early or late stages of infection. Cag T4SS activity for the initial 6 weeks of infection was sufficient for the development of gastric inflammation at the 3-month time point, with gastric cancer detected in a small proportion of animals. These experimental results, together with previous studies of cag mutant strains, provide strong evidence that Cag T4SS activity contributes to gastric carcinogenesis and help to define the stages of H. pylori infection during which Cag T4SS activity causes gastric alterations relevant for cancer pathogenesis. IMPORTANCE The “hit-and-run model” of carcinogenesis proposes that an infectious agent triggers carcinogenesis during initial stages of infection and that the ongoing presence of the infectious agent is not required for development of cancer. H. pylori infection and actions of CagA (an effector protein designated a bacterial oncoprotein, secreted by the Cag T4SS) are proposed to constitute a paradigm for hit-and-run carcinogenesis. In this study, we report the development of methods for controlling H. pylori Cag T4SS activity in vivo and demonstrate that Cag T4SS activity contributes to gastric carcinogenesis. We also show that Cag T4SS activity during an early stage of infection is sufficient to initiate a cascade of cellular alterations leading to gastric inflammation and gastric cancer at later time points.Aung Soe LinMark S. McClainAmber C. BeckettRhonda R. CastonM. Lorena HarveyBeverly R. E. A. DixonAnne M. CampbellJennifer H. B. ShumanNeha SawhneyAlberto G. DelgadoJohn T. LohM. Blanca PiazueloHolly M. Scott AlgoodTimothy L. CoverAmerican Society for MicrobiologyarticleHelicobacter pyloritype IV secretion systemgastric cancercarcinogenesisanimal modelhit-and-run hypothesisMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Helicobacter pylori type IV secretion system gastric cancer carcinogenesis animal model hit-and-run hypothesis Microbiology QR1-502
spellingShingle	Helicobacter pylori type IV secretion system gastric cancer carcinogenesis animal model hit-and-run hypothesis Microbiology QR1-502 Aung Soe Lin Mark S. McClain Amber C. Beckett Rhonda R. Caston M. Lorena Harvey Beverly R. E. A. Dixon Anne M. Campbell Jennifer H. B. Shuman Neha Sawhney Alberto G. Delgado John T. Loh M. Blanca Piazuelo Holly M. Scott Algood Timothy L. Cover Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis
description	ABSTRACT The Helicobacter pylori Cag type IV secretion system (T4SS) translocates the effector protein CagA and nonprotein bacterial constituents into host cells. In this study, we infected Mongolian gerbils with an H. pylori strain in which expression of the cagUT operon (required for Cag T4SS activity) is controlled by a TetR/tetO system. Transcript levels of cagU were significantly higher in gastric tissue from H. pylori-infected animals receiving doxycycline-containing chow (to derepress Cag T4SS activity) than in tissue from infected control animals receiving drug-free chow. At 3 months postinfection, infected animals receiving doxycycline had significantly increased gastric inflammation compared to infected control animals. Dysplasia (a premalignant histologic lesion) and/or invasive gastric adenocarcinoma were detected only in infected gerbils receiving doxycycline, not in infected control animals. We then conducted experiments in which Cag T4SS activity was derepressed during defined stages of infection. Continuous Cag T4SS activity throughout a 3-month time period resulted in higher rates of dysplasia and/or gastric cancer than observed when Cag T4SS activity was limited to early or late stages of infection. Cag T4SS activity for the initial 6 weeks of infection was sufficient for the development of gastric inflammation at the 3-month time point, with gastric cancer detected in a small proportion of animals. These experimental results, together with previous studies of cag mutant strains, provide strong evidence that Cag T4SS activity contributes to gastric carcinogenesis and help to define the stages of H. pylori infection during which Cag T4SS activity causes gastric alterations relevant for cancer pathogenesis. IMPORTANCE The “hit-and-run model” of carcinogenesis proposes that an infectious agent triggers carcinogenesis during initial stages of infection and that the ongoing presence of the infectious agent is not required for development of cancer. H. pylori infection and actions of CagA (an effector protein designated a bacterial oncoprotein, secreted by the Cag T4SS) are proposed to constitute a paradigm for hit-and-run carcinogenesis. In this study, we report the development of methods for controlling H. pylori Cag T4SS activity in vivo and demonstrate that Cag T4SS activity contributes to gastric carcinogenesis. We also show that Cag T4SS activity during an early stage of infection is sufficient to initiate a cascade of cellular alterations leading to gastric inflammation and gastric cancer at later time points.
format	article
author	Aung Soe Lin Mark S. McClain Amber C. Beckett Rhonda R. Caston M. Lorena Harvey Beverly R. E. A. Dixon Anne M. Campbell Jennifer H. B. Shuman Neha Sawhney Alberto G. Delgado John T. Loh M. Blanca Piazuelo Holly M. Scott Algood Timothy L. Cover
author_facet	Aung Soe Lin Mark S. McClain Amber C. Beckett Rhonda R. Caston M. Lorena Harvey Beverly R. E. A. Dixon Anne M. Campbell Jennifer H. B. Shuman Neha Sawhney Alberto G. Delgado John T. Loh M. Blanca Piazuelo Holly M. Scott Algood Timothy L. Cover
author_sort	Aung Soe Lin
title	Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis
title_short	Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis
title_full	Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis
title_fullStr	Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis
title_full_unstemmed	Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis
title_sort	temporal control of the <named-content content-type="genus-species">helicobacter pylori</named-content> cag type iv secretion system in a mongolian gerbil model of gastric carcinogenesis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/3791960f61674d22a55ee21aa1db0972
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Temporal Control of the <named-content content-type="genus-species">Helicobacter pylori</named-content> Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis

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