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PLoS Pathog. 2018 Feb 12;14(2):e1006862. doi: 10.1371/journal.ppat.1006862. eCollection 2018 Feb.

GM1 ganglioside-independent intoxication by Cholera toxin.

Author information

1
Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
2
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
3
Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
4
Department of Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
5
Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
6
Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
7
Mammalian Protein Expression Core Facility, University of Gothenburg, Gothenburg, Sweden.

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.

PMID:
29432456
PMCID:
PMC5825173
DOI:
10.1371/journal.ppat.1006862
[Indexed for MEDLINE]
Free PMC Article

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