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Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids

Authors
  • Cervin, Jakob1
  • Boucher, Andrew1
  • Youn, Gyusaang2
  • Björklund, Per3
  • Wallenius, Ville3
  • Mottram, Lynda1
  • Sampson, Nicole S.2
  • Yrlid, Ulf1
  • 1 University of Gothenburg, Sweden , (Sweden)
  • 2 Stony Brook University, United States , (United States)
  • 3 Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital/Östra, Sweden , (Sweden)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Mar 05, 2020
Volume
6
Issue
5
Pages
1192–1203
Identifiers
DOI: 10.1021/acsinfecdis.0c00009
PMID: 32134631
PMCID: PMC7227030
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, the CT B subunit (CTB) has a noncanonical site that binds fucosylated structures, which in contrast to GM1 are highly expressed in the human intestine. Here we evaluate the capacity of norbornene polymers displaying galactose and/or fucose to block CTB binding to immobilized protein-linked glycan structures and also to primary human and murine small intestine epithelial cells (SI ECs). We show that the binding of CTB to human SI ECs is largely dependent on the noncanonical binding site, and interference with the canonical site has a limited effect while the opposite is observed with murine SI ECs. The galactose–fucose polymer blocks binding to fucosylated glycans but not to GM1. However, the preincubation of CT with the galactose–fucose polymer only partially blocks toxic effects on cultured human enteroid cells, while preincubation with GM1 completely blocks CT-mediated secretion. Our results support a model whereby the binding of fucose to the noncanonical site places CT in close proximity to scarcely expressed galactose receptors such as GM1 to enable binding via the canonical site leading to CT internalization and intoxication. Our finding also highlights the importance of complementing CTB binding studies with functional intoxication studies when assessing the efficacy inhibitors of CT.

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