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GM1 ganglioside-independent intoxication by Cholera toxin

Journal article
Authors Jakob Cervin
Amberlyn M Wands
Anna Casselbrant
Han Wu
Soumya Krishnamurthy
Aleksander Cvjetkovic
Johanna Estelius
Benjamin Dedic
Anirudh Sethi
Kerri-Lee Wallom
Rebecca E Riise
Malin Bäckström
Ville Wallenius
Frances M Platt
Michael Lebens
Susann Teneberg
Lars Fändriks
Jennifer J Kohler
Ulf Yrlid
Published in PLoS Pathogens
Volume 14
Issue 2
ISSN 1553-7366
Publication year 2018
Published at Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Microbiology and Immunology
Core Facilities, Mammalian Protein Expression
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Institute of Clinical Sciences
Language en
Links dx.doi.org/10.1371/journal.ppat.100...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Immunobiology, Microbiology

Abstract

Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants.

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