GM1 ganglioside-independent intoxication by Cholera toxin

Jakob Cervin, Amberlyn M. Wands, Anna Casselbrant, Han Wu, Soumya Krishnamurthy, Aleksander Cvjetkovic, Johanna Estelius, Benjamin Dedic, Anirudh Sethi, Kerri Lee Wallom, Rebecca Riise, Malin Bäckström, Ville Wallenius, Frances M. Platt, Michael Lebens, Susann Teneberg, Lars Fändriks, Jennifer J. Kohler, Ulf Yrlid

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e1006862
JournalPLoS Pathogens
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

G(M1) Ganglioside
Cholera Toxin
Glycosphingolipids
Polysaccharides
Ceramides
Enterotoxins
Cell Surface Receptors
Oligosaccharides
Granulocytes
Knockout Mice
Glioma
Glycoproteins
Proteins
Epithelial Cells

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Cervin, J., Wands, A. M., Casselbrant, A., Wu, H., Krishnamurthy, S., Cvjetkovic, A., ... Yrlid, U. (2018). GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathogens, 14(2), e1006862. https://doi.org/10.1371/journal.ppat.1006862

GM1 ganglioside-independent intoxication by Cholera toxin. / Cervin, Jakob; Wands, Amberlyn M.; Casselbrant, Anna; Wu, Han; Krishnamurthy, Soumya; Cvjetkovic, Aleksander; Estelius, Johanna; Dedic, Benjamin; Sethi, Anirudh; Wallom, Kerri Lee; Riise, Rebecca; Bäckström, Malin; Wallenius, Ville; Platt, Frances M.; Lebens, Michael; Teneberg, Susann; Fändriks, Lars; Kohler, Jennifer J.; Yrlid, Ulf.

In: PLoS Pathogens, Vol. 14, No. 2, 01.02.2018, p. e1006862.

Research output: Contribution to journalArticle

Cervin, J, Wands, AM, Casselbrant, A, Wu, H, Krishnamurthy, S, Cvjetkovic, A, Estelius, J, Dedic, B, Sethi, A, Wallom, KL, Riise, R, Bäckström, M, Wallenius, V, Platt, FM, Lebens, M, Teneberg, S, Fändriks, L, Kohler, JJ & Yrlid, U 2018, 'GM1 ganglioside-independent intoxication by Cholera toxin', PLoS Pathogens, vol. 14, no. 2, pp. e1006862. https://doi.org/10.1371/journal.ppat.1006862
Cervin J, Wands AM, Casselbrant A, Wu H, Krishnamurthy S, Cvjetkovic A et al. GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathogens. 2018 Feb 1;14(2):e1006862. https://doi.org/10.1371/journal.ppat.1006862
Cervin, Jakob ; Wands, Amberlyn M. ; Casselbrant, Anna ; Wu, Han ; Krishnamurthy, Soumya ; Cvjetkovic, Aleksander ; Estelius, Johanna ; Dedic, Benjamin ; Sethi, Anirudh ; Wallom, Kerri Lee ; Riise, Rebecca ; Bäckström, Malin ; Wallenius, Ville ; Platt, Frances M. ; Lebens, Michael ; Teneberg, Susann ; Fändriks, Lars ; Kohler, Jennifer J. ; Yrlid, Ulf. / GM1 ganglioside-independent intoxication by Cholera toxin. In: PLoS Pathogens. 2018 ; Vol. 14, No. 2. pp. e1006862.
@article{4bbc6b00b3ec44d0aec027c6b91a041e,
title = "GM1 ganglioside-independent intoxication by Cholera toxin",
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.",
author = "Jakob Cervin and Wands, {Amberlyn M.} and Anna Casselbrant and Han Wu and Soumya Krishnamurthy and Aleksander Cvjetkovic and Johanna Estelius and Benjamin Dedic and Anirudh Sethi and Wallom, {Kerri Lee} and Rebecca Riise and Malin B{\"a}ckstr{\"o}m and Ville Wallenius and Platt, {Frances M.} and Michael Lebens and Susann Teneberg and Lars F{\"a}ndriks and Kohler, {Jennifer J.} and Ulf Yrlid",
year = "2018",
month = "2",
day = "1",
doi = "10.1371/journal.ppat.1006862",
language = "English (US)",
volume = "14",
pages = "e1006862",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - GM1 ganglioside-independent intoxication by Cholera toxin

AU - Cervin, Jakob

AU - Wands, Amberlyn M.

AU - Casselbrant, Anna

AU - Wu, Han

AU - Krishnamurthy, Soumya

AU - Cvjetkovic, Aleksander

AU - Estelius, Johanna

AU - Dedic, Benjamin

AU - Sethi, Anirudh

AU - Wallom, Kerri Lee

AU - Riise, Rebecca

AU - Bäckström, Malin

AU - Wallenius, Ville

AU - Platt, Frances M.

AU - Lebens, Michael

AU - Teneberg, Susann

AU - Fändriks, Lars

AU - Kohler, Jennifer J.

AU - Yrlid, Ulf

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85046889144&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046889144&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1006862

DO - 10.1371/journal.ppat.1006862

M3 - Article

C2 - 29432456

AN - SCOPUS:85046889144

VL - 14

SP - e1006862

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 2

ER -