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

Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways.
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Bridge DR, Blum FC, Jang S, Kim J, Cha JH, Merrell DS,


Bridge DR, Blum FC, Jang S, Kim J, Cha JH, Merrell DS, (click to view)

Bridge DR, Blum FC, Jang S, Kim J, Cha JH, Merrell DS,

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Scientific reports 2017 09 087(1) 11057 doi 10.1038/s41598-017-11382-y
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.

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