title: CD44 Promotes intoxication by the clostridial iota-family toxins.
abstract: Various pathogenic clostridia produce binary protein toxins associated with enteric diseases of humans and animals. Separate binding/translocation (B) components bind to a protein receptor on the cell surface, assemble with enzymatic (A) component(s), and mediate endocytosis of the toxin complex. Ultimately there is translocation of A component(s) from acidified endosomes into the cytosol, leading to destruction of the actin cytoskeleton. Our results revealed that CD44, a multifunctional surface protein of mammalian cells, facilitates intoxication by the iota family of clostridial binary toxins. Specific antibody against CD44 inhibited cytotoxicity of the prototypical Clostridium perfringens iota toxin. Versus CD44(+) melanoma cells, those lacking CD44 bound less toxin and were dose-dependently resistant to C. perfringens iota, as well as Clostridium difficile and Clostridium spiroforme iota-like, toxins. Purified CD44 specifically interacted in vitro with iota and iota-like, but not related Clostridium botulinum C2, toxins. Furthermore, CD44 knockout mice were resistant to iota toxin lethality. Collective data reveal an important role for CD44 during intoxication by a family of clostridial binary toxins.
authors.affiliation: Integrated Toxicology Division, Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Darran J
authors.initials: DJ
authors.lastname: Wigelsworth
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.forename: Leonie
authors.initials: L
authors.lastname: Schnell
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.forename: Josip
authors.initials: J
authors.lastname: Blonder
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Carman
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Wilkins
authors.forename: Guy Tran
authors.initials: GT
authors.lastname: Van Nhieu
authors.forename: Serge
authors.initials: S
authors.lastname: Pauillac
authors.forename: Maryse
authors.initials: M
authors.lastname: Gibert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sauvonnet
authors.forename: Bradley G
authors.initials: BG
authors.lastname: Stiles
authors.forename: Michel R
authors.initials: MR
authors.lastname: Popoff
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
mesh_terms: D036002:ADP Ribose Transferases / Q000633:toxicity*; D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D014709:Vero Cells
chemical_list: D001427:Bacterial Toxins; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C050737:iota toxin, Clostridium perfringens; D036002:ADP Ribose Transferases; D004229:Dithiothreitol