title: Assessment in mice of the therapeutic potential of tailored, multivalent Shiga toxin carbohydrate ligands.
abstract: The therapeutic potential of 2 soluble multivalent receptor-based inhibitors of Shiga toxin (Stx) 1 and Stx2 was determined in mice. One of these, Starfish, protected mice when it was injected subcutaneously in admixture with a lethal dose of Stx1 but not Stx2. Starfish also reduced the distribution of (125)I-Stx1 but not (125)I-Stx2 to the murine kidney and brain. A modified version of Starfish, called "Daisy," in which the Stx alpha Gal(1,4)beta Gal(1,4)beta Glc receptors were installed on the core glucose structure via a modified tethering strategy, protected mice against both Stx1 and Stx2. Daisy also protected streptomycin-treated mice from Escherichia coli O91:H21 and did not interfere with the ability of the murine immune system to produce Stx-specific protective antibodies. These results extend the possibility of using soluble carbohydrate-based receptor inhibitors to prevent Stx-mediated complications arising from infections with enterohemorrhagic E. coli serotypes.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
authors.forename: George L
authors.initials: GL
authors.lastname: Mulvey
authors.forename: Paola
authors.initials: P
authors.lastname: Marcato
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Kitov
authors.forename: Joanna
authors.initials: J
authors.lastname: Sadowska
authors.forename: David R
authors.initials: DR
authors.lastname: Bundle
authors.forename: Glen D
authors.initials: GD
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000907:Antibodies, Bacterial / Q000097:blood; D000992:Antitoxins / Q000627:therapeutic use*; D002240:Carbohydrate Sequence; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D015151:Immunoblotting; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D022622:Shiga Toxin 1 / Q000037:antagonists & inhibitors; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors; D013307:Streptomycin / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000992:Antitoxins; C472587:Daisy carbohydrate; D009844:Oligosaccharides; C404684:STARFISH carbohydrate; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2; D013307:Streptomycin