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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Curie Institute, Paris
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Artikelnummer14362
TidskriftScientific Reports
Volym9
Utgåva nummer1
StatusPublished - 2019
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Karl Johansson, 2020, Lund: Lund University, Faculty of Medicine. 73 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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