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Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-B Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells¹

Alain P. Gobert^2,*, Marjolaine Vareille^*, Anne-Lise Glasser, Thomas Hindré^*, Thibaut de Sablet^* and Christine Martin^*

^* Institut National de la Recherche Argonomique, UR454 Unité de Microbiologie, Centre de Theix, Saint-Genès-Champanelle, France; and Pathogénie Bactérienne Intestinale, Laboratoire de Bactériologie, USC Institut National de la Recherche Argonomique 2018, Université d’Auvergne, CBRV, Clermont-Ferrand, France

Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli (EHEC) binds to endothelial cells expressing globotriaosylceramide-3 (Gb-3) and induces cell death by inhibiting translation. Nonetheless, the effects of Stx on human enterocytes, which lacks receptor Gb-3, remain less known. In this study, we questioned whether EHEC-derived Stx may modulate cellular signalization in the Gb-3-negative human epithelial cell line T84. Stx produced by EHEC was fixed and internalized by the cells. A weak activation of NF-B was observed in T84 cells after EHEC infection. Cells infected with an isogenic mutant lacking stx1 and stx2, the genes encoding Stx, displayed an increased NF-B DNA-binding activity. Consequently, the NF-B-dependent CCL20 and IL-8 gene transcription and chemokine production were enhanced in T84 cells infected with the Stx mutant in comparison to the wild-type strain. Investigating the mechanism by which Stx modulates NF-B activation, we showed that the PI3K/Akt signaling pathway was not induced by EHEC but was enhanced by the strain lacking Stx. Pharmacological inhibition of the PI3K/Akt signalization in EHEC Stx-infected T84 cells yielded to a complete decrease of NF-B activation and CCL20 and IL-8 mRNA expression. This demonstrates that the induction of the PI3K/Akt/NF-B pathway is potentially induced by EHEC, but is inhibited by Stx in Gb-3-negative epithelial cells. Thus, Stx is an unrecognized modulator of the innate immune response of human enterocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Institut de la Recherche Agronomique (to M.V. and T.H.) and from Région Auvergne (to M.V.).

² Address correspondence and reprint requests to Dr. Alain P. Gobert, Unité de Microbiologie, Institut National de la Recherche Argonomique, Centre de Theix, 63122 Saint-Genès-Champanelle, France. E-mail address: agobert{at}clermont.inra.fr

³ Abbreviations used in this paper: STEC, Shiga toxin-producing Escherichia coli; HUS, hemolytic-uremic syndrome; EHEC, enterohaemorrhagic Escherichia coli; Stx, Shiga toxin; Gb-3, globotriaosylceramide-3; WT, wild type; DAPI, 4',6'-diamidino-2-phenylindole.

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