Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism.
Adenosine Triphosphate
/ metabolism
Animals
Benzenesulfonates
/ pharmacology
Blood Platelets
/ microbiology
Enterohemorrhagic Escherichia coli
/ drug effects
Escherichia coli Infections
/ drug therapy
HeLa Cells
Hemolytic-Uremic Syndrome
/ drug therapy
Humans
Mice
Purinergic P2X Receptor Antagonists
/ pharmacology
Receptors, Purinergic P2X1
/ genetics
Shiga Toxin
/ antagonists & inhibitors
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
07 10 2019
07 10 2019
Historique:
received:
20
06
2019
accepted:
17
09
2019
entrez:
9
10
2019
pubmed:
9
10
2019
medline:
30
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31591425
doi: 10.1038/s41598-019-50692-1
pii: 10.1038/s41598-019-50692-1
pmc: PMC6779916
doi:
Substances chimiques
4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate)
0
Benzenesulfonates
0
Purinergic P2X Receptor Antagonists
0
Receptors, Purinergic P2X1
0
Shiga Toxin
75757-64-1
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14362Références
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