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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.

Authors

Carrie A. Cowardin

Erica L. Buonomo

Mahmoud M. Saleh

Madeline G. Wilson

Stacey L. Burgess

Carsten Schwan

Sarah A. Kuehne

Anna M. Eichhoff

Friedrich Koch-Nolte

Dena Lyras

Klaus Aktories

William A. Petri



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.

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