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

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

Abstract

© 2016 Macmillan Publishers Limited. All rights reserved. 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.

Citation

Cowardin, C. A., Buonomo, E. L., Saleh, M. M., Wilson, M. G., Burgess, S. L., Schwan, C., …Petri, W. A. (2016). The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nature Microbiology, 1(8), Article 16108. https://doi.org/10.1038/nmicrobiol.2016.108

• Journal Article Type: Article
• Acceptance Date: Jun 1, 2016
• Online Publication Date: Jul 11, 2016
• Publication Date: Jul 11, 2016
• Deposit Date: Feb 19, 2019
• Journal: Nature Microbiology
• Electronic ISSN: 2058-5276
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 1
• Issue: 8
• Article Number: 16108
• DOI: https://doi.org/10.1038/nmicrobiol.2016.108
• Public URL: https://nottingham-repository.worktribe.com/output/1566816
• Publisher URL: https://www.nature.com/articles/nmicrobiol2016108