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

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

Research output: Contribution to journalArticleResearchpeer-review

54 Citations (Scopus)

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.

Original languageEnglish
Article number16108
Number of pages10
JournalNature Microbiology
Volume1
Issue number8
DOIs
Publication statusPublished - 11 Jul 2016

Keywords

  • bacterial immune evasion
  • bacterial pathogenesis
  • Clostridium difficile
  • infection
  • innate immunity

Cite this

Cowardin, C. A., Buonomo, E. L., Saleh, M. M., Wilson, M. G., Burgess, S. L., Kuehne, S. A., ... Petri, W. A. (2016). The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nature Microbiology, 1(8), [16108]. https://doi.org/10.1038/nmicrobiol.2016.108
Cowardin, Carrie A. ; Buonomo, Erica L. ; Saleh, Mahmoud M. ; Wilson, Madeline G. ; Burgess, Stacey L. ; Kuehne, Sarah A. ; Schwan, Carsten ; Eichhoff, Anna M. ; Koch-Nolte, Friedrich ; Lyras, Dena ; Aktories, Klaus ; Minton, Nigel P. ; Petri, William A. / The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. In: Nature Microbiology. 2016 ; Vol. 1, No. 8.
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Cowardin, CA, Buonomo, EL, Saleh, MM, Wilson, MG, Burgess, SL, Kuehne, SA, Schwan, C, Eichhoff, AM, Koch-Nolte, F, Lyras, D, Aktories, K, Minton, NP & Petri, WA 2016, 'The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia', Nature Microbiology, vol. 1, no. 8, 16108. https://doi.org/10.1038/nmicrobiol.2016.108

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.; Kuehne, Sarah A.; Schwan, Carsten; Eichhoff, Anna M.; Koch-Nolte, Friedrich; Lyras, Dena; Aktories, Klaus; Minton, Nigel P.; Petri, William A.

In: Nature Microbiology, Vol. 1, No. 8, 16108, 11.07.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia

AU - Cowardin, Carrie A.

AU - Buonomo, Erica L.

AU - Saleh, Mahmoud M.

AU - Wilson, Madeline G.

AU - Burgess, Stacey L.

AU - Kuehne, Sarah A.

AU - Schwan, Carsten

AU - Eichhoff, Anna M.

AU - Koch-Nolte, Friedrich

AU - Lyras, Dena

AU - Aktories, Klaus

AU - Minton, Nigel P.

AU - Petri, William A.

PY - 2016/7/11

Y1 - 2016/7/11

N2 - 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.

AB - 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.

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KW - bacterial pathogenesis

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KW - infection

KW - innate immunity

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DO - 10.1038/nmicrobiol.2016.108

M3 - Article

VL - 1

JO - Nature Microbiology

JF - Nature Microbiology

SN - 2058-5276

IS - 8

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ER -