Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism

Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli (EHEC), that cause gastrointestinal infection leading to hemolytic uremic syndrome. The aim of this study was to investigate if Stx signals via ATP and if blockade of purinergic receptors could be protective. Stx in...

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Autores principales: Johansson, Karl E., Ståhl, Anne-Lie, Arvidsson, Ida, Loos, Sebastian, Tontanahal, Ashmita, Rebetz, Johan, Chromek, Milan, Kristoffersson, Ann-Charlotte, Johannes, Ludger, Karpman, Diana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779916/
https://www.ncbi.nlm.nih.gov/pubmed/31591425
http://dx.doi.org/10.1038/s41598-019-50692-1
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author Johansson, Karl E.
Ståhl, Anne-Lie
Arvidsson, Ida
Loos, Sebastian
Tontanahal, Ashmita
Rebetz, Johan
Chromek, Milan
Kristoffersson, Ann-Charlotte
Johannes, Ludger
Karpman, Diana
author_facet Johansson, Karl E.
Ståhl, Anne-Lie
Arvidsson, Ida
Loos, Sebastian
Tontanahal, Ashmita
Rebetz, Johan
Chromek, Milan
Kristoffersson, Ann-Charlotte
Johannes, Ludger
Karpman, Diana
author_sort Johansson, Karl E.
collection PubMed
description Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli (EHEC), that cause gastrointestinal infection leading to hemolytic uremic syndrome. The aim of this study was to investigate if Stx signals via ATP and if blockade of purinergic receptors could be protective. Stx induced ATP release from HeLa cells and in a mouse model. Toxin induced rapid calcium influx into HeLa cells, as well as platelets, and a P2X1 receptor antagonist, NF449, abolished this effect. Likewise, the P2X antagonist suramin blocked calcium influx in Hela cells. NF449 did not affect toxin intracellular retrograde transport, however, cells pre-treated with NF449 exhibited significantly higher viability after exposure to Stx for 24 hours, compared to untreated cells. NF449 protected HeLa cells from protein synthesis inhibition and from Stx-induced apoptosis, assayed by caspase 3/7 activity. The latter effect was confirmed by P2X1 receptor silencing. Stx induced the release of toxin-positive HeLa cell- and platelet-derived microvesicles, detected by flow cytometry, an effect significantly reduced by NF449 or suramin. Suramin decreased microvesicle levels in mice injected with Stx or inoculated with Stx-producing EHEC. Taken together, we describe a novel mechanism of Stx-mediated cellular injury associated with ATP signaling and inhibited by P2X receptor blockade.
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spelling pubmed-67799162019-10-16 Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism Johansson, Karl E. Ståhl, Anne-Lie Arvidsson, Ida Loos, Sebastian Tontanahal, Ashmita Rebetz, Johan Chromek, Milan Kristoffersson, Ann-Charlotte Johannes, Ludger Karpman, Diana Sci Rep Article Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli (EHEC), that cause gastrointestinal infection leading to hemolytic uremic syndrome. The aim of this study was to investigate if Stx signals via ATP and if blockade of purinergic receptors could be protective. Stx induced ATP release from HeLa cells and in a mouse model. Toxin induced rapid calcium influx into HeLa cells, as well as platelets, and a P2X1 receptor antagonist, NF449, abolished this effect. Likewise, the P2X antagonist suramin blocked calcium influx in Hela cells. NF449 did not affect toxin intracellular retrograde transport, however, cells pre-treated with NF449 exhibited significantly higher viability after exposure to Stx for 24 hours, compared to untreated cells. NF449 protected HeLa cells from protein synthesis inhibition and from Stx-induced apoptosis, assayed by caspase 3/7 activity. The latter effect was confirmed by P2X1 receptor silencing. Stx induced the release of toxin-positive HeLa cell- and platelet-derived microvesicles, detected by flow cytometry, an effect significantly reduced by NF449 or suramin. Suramin decreased microvesicle levels in mice injected with Stx or inoculated with Stx-producing EHEC. Taken together, we describe a novel mechanism of Stx-mediated cellular injury associated with ATP signaling and inhibited by P2X receptor blockade. Nature Publishing Group UK 2019-10-07 /pmc/articles/PMC6779916/ /pubmed/31591425 http://dx.doi.org/10.1038/s41598-019-50692-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Johansson, Karl E.
Ståhl, Anne-Lie
Arvidsson, Ida
Loos, Sebastian
Tontanahal, Ashmita
Rebetz, Johan
Chromek, Milan
Kristoffersson, Ann-Charlotte
Johannes, Ludger
Karpman, Diana
Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
title Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
title_full Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
title_fullStr Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
title_full_unstemmed Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
title_short Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
title_sort shiga toxin signals via atp and its effect is blocked by purinergic receptor antagonism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779916/
https://www.ncbi.nlm.nih.gov/pubmed/31591425
http://dx.doi.org/10.1038/s41598-019-50692-1
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