Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells

Amberlyn M. Wands, Jakob Cervin, He Huang, Ye Zhang, Gyusaang Youn, Chad A. Brautigam, Maria Matson Dzebo, Per Björklund, Ville Wallenius, Danielle K. Bright, Clay S. Bennett, Pernilla Wittung-Stafshede, Nicole S. Sampson, Ulf Yrlid, Jennifer J. Kohler

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin. Further, l-fucose can competively inhibit CTB binding to intestinal epithelia cells. Here, we use competition binding assays with l-fucose analogs to decipher the molecular determinants for l-fucose inhibition of cholera toxin subunit B (CTB) binding. Additionally, we find that mono- and difucosylated oligosaccharides are more potent inhibitors than l-fucose alone, with the LeY tetrasaccharide emerging as the most potent inhibitor of CTB binding to two colonic epithelial cell lines (T84 and Colo205). Finally, a non-natural fucose-containing polymer inhibits CTB binding two orders of magnitude more potently than the LeY glycan when tested against Colo205 cells. This same polymer also inhibits CTB binding to T84 cells and primary human jejunal epithelial cells in a dose-dependent manner. These findings suggest the possibility that polymeric display of fucose might be exploited as a prophylactic or therapeutic approach to block the action of CT toward the human intestinal epithelium.

Original languageEnglish (US)
Pages (from-to)758-770
Number of pages13
JournalACS Infectious Diseases
Volume4
Issue number5
DOIs
StatePublished - May 11 2018

Fingerprint

Cholera Toxin
Fucose
Intestinal Mucosa
Epithelial Cells
Polysaccharides
Polymers
Cell Line
Cell Surface Receptors
Oligosaccharides
Dehydration
Cytosol
Electrolytes
Epitopes
Glycoproteins

Keywords

  • cholera toxin
  • fucose
  • gangliosides
  • glycoproteins
  • human milk oligosaccharides (HMOs)
  • ring-opening metathesis polymerization (ROMP)

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells. / Wands, Amberlyn M.; Cervin, Jakob; Huang, He; Zhang, Ye; Youn, Gyusaang; Brautigam, Chad A.; Matson Dzebo, Maria; Björklund, Per; Wallenius, Ville; Bright, Danielle K.; Bennett, Clay S.; Wittung-Stafshede, Pernilla; Sampson, Nicole S.; Yrlid, Ulf; Kohler, Jennifer J.

In: ACS Infectious Diseases, Vol. 4, No. 5, 11.05.2018, p. 758-770.

Research output: Contribution to journalArticle

Wands, AM, Cervin, J, Huang, H, Zhang, Y, Youn, G, Brautigam, CA, Matson Dzebo, M, Björklund, P, Wallenius, V, Bright, DK, Bennett, CS, Wittung-Stafshede, P, Sampson, NS, Yrlid, U & Kohler, JJ 2018, 'Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells', ACS Infectious Diseases, vol. 4, no. 5, pp. 758-770. https://doi.org/10.1021/acsinfecdis.7b00085
Wands, Amberlyn M. ; Cervin, Jakob ; Huang, He ; Zhang, Ye ; Youn, Gyusaang ; Brautigam, Chad A. ; Matson Dzebo, Maria ; Björklund, Per ; Wallenius, Ville ; Bright, Danielle K. ; Bennett, Clay S. ; Wittung-Stafshede, Pernilla ; Sampson, Nicole S. ; Yrlid, Ulf ; Kohler, Jennifer J. / Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells. In: ACS Infectious Diseases. 2018 ; Vol. 4, No. 5. pp. 758-770.
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abstract = "Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin. Further, l-fucose can competively inhibit CTB binding to intestinal epithelia cells. Here, we use competition binding assays with l-fucose analogs to decipher the molecular determinants for l-fucose inhibition of cholera toxin subunit B (CTB) binding. Additionally, we find that mono- and difucosylated oligosaccharides are more potent inhibitors than l-fucose alone, with the LeY tetrasaccharide emerging as the most potent inhibitor of CTB binding to two colonic epithelial cell lines (T84 and Colo205). Finally, a non-natural fucose-containing polymer inhibits CTB binding two orders of magnitude more potently than the LeY glycan when tested against Colo205 cells. This same polymer also inhibits CTB binding to T84 cells and primary human jejunal epithelial cells in a dose-dependent manner. These findings suggest the possibility that polymeric display of fucose might be exploited as a prophylactic or therapeutic approach to block the action of CT toward the human intestinal epithelium.",
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AU - Wands, Amberlyn M.

AU - Cervin, Jakob

AU - Huang, He

AU - Zhang, Ye

AU - Youn, Gyusaang

AU - Brautigam, Chad A.

AU - Matson Dzebo, Maria

AU - Björklund, Per

AU - Wallenius, Ville

AU - Bright, Danielle K.

AU - Bennett, Clay S.

AU - Wittung-Stafshede, Pernilla

AU - Sampson, Nicole S.

AU - Yrlid, Ulf

AU - Kohler, Jennifer J.

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N2 - Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin. Further, l-fucose can competively inhibit CTB binding to intestinal epithelia cells. Here, we use competition binding assays with l-fucose analogs to decipher the molecular determinants for l-fucose inhibition of cholera toxin subunit B (CTB) binding. Additionally, we find that mono- and difucosylated oligosaccharides are more potent inhibitors than l-fucose alone, with the LeY tetrasaccharide emerging as the most potent inhibitor of CTB binding to two colonic epithelial cell lines (T84 and Colo205). Finally, a non-natural fucose-containing polymer inhibits CTB binding two orders of magnitude more potently than the LeY glycan when tested against Colo205 cells. This same polymer also inhibits CTB binding to T84 cells and primary human jejunal epithelial cells in a dose-dependent manner. These findings suggest the possibility that polymeric display of fucose might be exploited as a prophylactic or therapeutic approach to block the action of CT toward the human intestinal epithelium.

AB - Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin. Further, l-fucose can competively inhibit CTB binding to intestinal epithelia cells. Here, we use competition binding assays with l-fucose analogs to decipher the molecular determinants for l-fucose inhibition of cholera toxin subunit B (CTB) binding. Additionally, we find that mono- and difucosylated oligosaccharides are more potent inhibitors than l-fucose alone, with the LeY tetrasaccharide emerging as the most potent inhibitor of CTB binding to two colonic epithelial cell lines (T84 and Colo205). Finally, a non-natural fucose-containing polymer inhibits CTB binding two orders of magnitude more potently than the LeY glycan when tested against Colo205 cells. This same polymer also inhibits CTB binding to T84 cells and primary human jejunal epithelial cells in a dose-dependent manner. These findings suggest the possibility that polymeric display of fucose might be exploited as a prophylactic or therapeutic approach to block the action of CT toward the human intestinal epithelium.

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KW - human milk oligosaccharides (HMOs)

KW - ring-opening metathesis polymerization (ROMP)

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