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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Helicobacter pylori vacA genotype is a predominant determinant of immune response to Helicobacter pylori CagA
Alexander Link, Cosima Langner, Wiebke Schirrmeister, Wiebke Habendorf, Jochen Weigt, Marino Venerito, Ina Tammer, Dirk Schlüter, Philipp Schlaermann, Thomas F Meyer, Thomas Wex, Peter Malfertheiner
Alexander Link, Cosima Langner, Wiebke Schirrmeister, Wiebke Habendorf, Jochen Weigt, Marino Venerito, Thomas Wex, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, 39120 Magdeburg, Germany
Ina Tammer, Dirk Schlüter, Institute of Medical Microbiology, Otto-von-Guericke University, Magdeburg, 39120 Magdeburg, Germany
Philipp Schlaermann, Thomas F Meyer, Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany
Thomas Wex, Department of Molecular Genetics, Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, 39124 Magdeburg, Germany
Dirk Schlüter, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany
Author contributions: Link A and Langner C contributed equally to this work; Link A, Wex T and Malfertheiner P designed the research; Link A, Langner C, Schirrmeister W, Habendorf W, Tammer I, Schlaermann P and Wex T performed the research; Link A, Schirrmeister W and Schlaermann P contributed new reagents/analytic tools; Link A, Langner C, Schlaermann P, Wex T and Malfertheiner P analyzed the data; Link A, Langner C and Malfertheiner P wrote the paper; all authors revised and approved the final version of the paper.
Supported by the BMBF No. BMBF-0315905D in the frame of ERA-NET PathoGenoMics to Malfertheiner P.
Institutional review board statement: The study was reviewed and approved by the ethical board of the Otto-von-Guericke University (Study Number 80/11).
Informed consent statement: All patients provided written informed consent before inclusion in the study.
Conflict-of-interest statement: The authors have no conflicts to declare.
Data sharing statement: Technical appendix and dataset available from the corresponding author: alexander.link@med.ovgu.de. Participants gave informed consent for data analysis and publication. Since no patients consent to data sharing was obtained, no additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Alexander Link, MD, PhD, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
alexander.link@med.ovgu.de
Telephone: +49-391-6713100 Fax: +49-391-6713105
Received: January 19, 2017
Peer-review started: January 22, 2017
First decision: March 16, 2017
Revised: April 5, 2017
Accepted: May 19, 2017
Article in press: May 19, 2017
Published online: July 14, 2017
Processing time: 173 Days and 7 Hours
AIM
To evaluate the frequency of Helicobacter pylori (H. pylori) CagA antibodies in H. pylori infected subjects and to identify potential histopathological and bacterial factors related to H. pylori CagA-immune response.
METHODS
Systematic data to H. pylori isolates, blood samples, gastric biopsies for histological and molecular analyses were available from 99 prospectively recruited subjects. Serological profile (anti-H. pylori, anti-CagA) was correlated with H. pylori isolates (cagA, EPIYA, vacA s/m genotype), histology (Sydney classification) and mucosal interleukin-8 (IL-8) mRNA and protein expression. Selected H. pylori strains were assessed for H. pylori CagA protein expression and IL-8 induction in co-cultivation model with AGS cells.
RESULTS
Thirty point three percent of microbiologically confirmed H. pylori infected patients were seropositive for CagA. Majority of H. pylori isolates were cagA gene positive (93.9%) with following vacA polymorphisms: 42.4% vacA s1m1, 23.2% s1m2 and 34.3% s2m2. Anti-CagA-IgG seropositivity was strongly associated with atrophic gastritis, increased mucosal inflammation according to the Sydney score, IL-8 and cagA mRNA expression. VacA s and m polymorphisms were the major determinants for positive (vacA s1m1) or negative (vacA s2m2) anti-CagA serological immune response, which also correlated with the in vitro inflammatory potential in AGS cells. In vitro co-cultivation of representative H. pylori strains with AGS cells confirmed functional CagA translocation, which showed only partial correlation with CagA seropositivity in patients, supporting vacA as major co-determinant of the immune response.
CONCLUSION
Serological immune response to H. pylori cagA+ strain in H. pylori infected patients is strongly associated with vacA polymorphism, suggesting the crucial role of bacterial factors in immune and clinical phenotype of the infection.
Core tip:Helicobacter pylori (H. pylori) related diseases are commonly associated with cagA+ strains, although seropositivity against CagA varies among different studies. In this prospective study, we evaluated potential factors related to the H. pylori CagA-immune response. We show that anti-CagA-IgG seropositivity was strongly associated with histopathological and inflammatory factors. Most importantly, we identified H. pylori vacA polymorphism as one of the main determinants of immune response to CagA and inflammatory potential of H. pylori strains ex vivo and in vitro. Our data support the crucial role of bacterial factors that co-determine the complex interaction with H. pylori and define the immune and clinical phenotypes of the infection.
