Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways

Dacie R. Bridge; Faith C. Blum; Sungil Jang; Jinmoon Kim; Jeong Heon Cha; D. Scott Merrell

doi:10.1038/s41598-017-11382-y

Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways

Dacie R. Bridge, Faith C. Blum, Sungil Jang, Jinmoon Kim, Jeong Heon Cha, D. Scott Merrell

Department of Oral Biology

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-Terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-Terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development.

Original language	English
Article number	11057
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-11382-y
Publication status	Published - 2017 Dec 1

Bibliographical note

Funding Information:
We would like to thank Dr. Beth M. Carpenter and Jeannette M. Whitmire for technical assistance with the isogenic strain construction and Dr. Cara Olsen for help with the statistical analyses. We would also like to thank members of the Merrell laboratory for helpful discussion of the results of the study. This work was supported by National Institutes of Health R21AI109405 to D.S.M., Mid-Atlantic Regional Center for Excellence Grant 2 U54 AI57168–06 to D.S.M., and an Uniformed Services University of the Health Sciences award to D.R.B. The contents of this manuscript are solely those of the authors and do not reflect the views of the National Institutes of Health or the Department of Defense.

Publisher Copyright:
© 2017 The Author(s).

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title = "Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways",

abstract = "The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-Terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-Terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development.",

author = "Bridge, {Dacie R.} and Blum, {Faith C.} and Sungil Jang and Jinmoon Kim and Cha, {Jeong Heon} and Merrell, {D. Scott}",

note = "Funding Information: We would like to thank Dr. Beth M. Carpenter and Jeannette M. Whitmire for technical assistance with the isogenic strain construction and Dr. Cara Olsen for help with the statistical analyses. We would also like to thank members of the Merrell laboratory for helpful discussion of the results of the study. This work was supported by National Institutes of Health R21AI109405 to D.S.M., Mid-Atlantic Regional Center for Excellence Grant 2 U54 AI57168–06 to D.S.M., and an Uniformed Services University of the Health Sciences award to D.R.B. The contents of this manuscript are solely those of the authors and do not reflect the views of the National Institutes of Health or the Department of Defense. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Cha, Jeong Heon

AU - Merrell, D. Scott

N1 - Funding Information: We would like to thank Dr. Beth M. Carpenter and Jeannette M. Whitmire for technical assistance with the isogenic strain construction and Dr. Cara Olsen for help with the statistical analyses. We would also like to thank members of the Merrell laboratory for helpful discussion of the results of the study. This work was supported by National Institutes of Health R21AI109405 to D.S.M., Mid-Atlantic Regional Center for Excellence Grant 2 U54 AI57168–06 to D.S.M., and an Uniformed Services University of the Health Sciences award to D.R.B. The contents of this manuscript are solely those of the authors and do not reflect the views of the National Institutes of Health or the Department of Defense. Publisher Copyright: © 2017 The Author(s).

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N2 - The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-Terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-Terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development.

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ER -

Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways

Abstract

Bibliographical note

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UN SDGs

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