CD44 Promotes intoxication by the clostridial iota-family toxins

PLoS One. 2012;7(12):e51356. doi: 10.1371/journal.pone.0051356. Epub 2012 Dec 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / toxicity*
  • Animals
  • Bacterial Toxins / toxicity*
  • Blotting, Western
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Dithiothreitol / pharmacology
  • Dose-Response Relationship, Drug
  • Endocytosis / physiology*
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Vero Cells

Substances

  • Bacterial Toxins
  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • iota toxin, Clostridium perfringens
  • ADP Ribose Transferases
  • Dithiothreitol

Grants and funding

Funding was provided in part by the Institut Pasteur (MRP), Faculty Fund for Research at Wilson College (BGS), as well as the Faculty of Medicine at the University of Ulm plus Deutsche Forschungsgemeinschaft (DFG grant BA 2087/2-1) to HB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.