The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia

Research output: Contribution to journalArticle

Authors

  • Carrie A Cowardin
  • Erica L Buonomo
  • Mahmoud M Saleh
  • Madeline G Wilson
  • Stacey L Burgess
  • Carsten Schwan
  • Anna M Eichhoff
  • Friedrich Koch-Nolte
  • Dena Lyras
  • Klaus Aktories
  • Nigel P Minton
  • William A Petri

Colleges, School and Institutes

External organisations

  • Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.
  • Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre (SBRC), School of Life Sciences, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
  • Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • Institute of Immunology, University Medical Center Hamburg-Eppendorf, D20246 Hamburg, Germany.
  • Department of Microbiology, Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Monash University, Victoria 3800, Australia.

Abstract

Clostridium difficile is the most common hospital acquired pathogen in the USA, and infection is, in many cases, fatal. Toxins A and B are its major virulence factors, but expression of a third toxin, known as C. difficile transferase (CDT), is increasingly common. An adenosine diphosphate (ADP)-ribosyltransferase that causes actin cytoskeletal disruption, CDT is typically produced by the major, hypervirulent strains and has been associated with more severe disease. Here, we show that CDT enhances the virulence of two PCR-ribotype 027 strains in mice. The toxin induces pathogenic host inflammation via a Toll-like receptor 2 (TLR2)-dependent pathway, resulting in the suppression of a protective host eosinophilic response. Finally, we show that restoration of TLR2-deficient eosinophils is sufficient for protection from a strain producing CDT. These findings offer an explanation for the enhanced virulence of CDT-expressing C. difficile and demonstrate a mechanism by which this binary toxin subverts the host immune response.

Details

Original languageEnglish
Article number16108
JournalNature Microbiology
Volume1
Issue number8
Publication statusPublished - 11 Jul 2016

Keywords

  • Journal Article