Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells
Artikel i vetenskaplig tidskrift, 2018

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.

ring-opening metathesis polymerization (ROMP)

gangliosides

glycoproteins

human milk oligosaccharides (HMOs)

fucose

cholera toxin

Författare

Amberlyn M. Wands

UT Southwestern Medical School

Jakob Cervin

Göteborgs universitet

He Huang

Stony Brook University

Ye Zhang

Stony Brook University

Gyusaang Youn

Stony Brook University

Chad A. Brautigam

University of Texas at Dallas

Maria Matson Dzebo

Chalmers, Biologi och bioteknik, Kemisk biologi

Per Björklund

Sahlgrenska universitetssjukhuset

Ville Wallenius

Sahlgrenska universitetssjukhuset

Danielle K. Bright

Tufts University

Clay S. Bennett

Tufts University

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi

Nicole S. Sampson

Stony Brook University

Ulf Yrlid

Göteborgs universitet

Jennifer J. Kohler

UT Southwestern Medical School

ACS Infectious Diseases

2373-8227 (eISSN)

Vol. 4 758-770

Ämneskategorier

Cellbiologi

Immunologi inom det medicinska området

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1021/acsinfecdis.7b00085