Advanced search
1 file | 1.63 MB

Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis

Author
Organization
Abstract
Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. Additionally, TcdA and TcdB engage the Pyrin inflammasome in macrophages, but whether Pyrin modulates CDI pathophysiology is unknown. Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase-3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo.
Keywords
A-INDUCED APOPTOSIS, PYRIN INFLAMMASOME ACTIVATION, INTERLEUKIN-8 GENE, PROMOTER, TOXIN-B, RHO-GTPASES, GASDERMIN D, COMMON POLYMORPHISM, PROTEIN-KINASE, IN-VIVO, DEATH

Downloads

  • 4074 18Saavedra.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 1.63 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Saavedra, Pedro Henrique Viana, Linyan Huang, Farzaneh Ghazavi, Stephanie Kourula, Tom Vanden Berghe, Nozomi Takahashi, Peter Vandenabeele, and Mohamed Lamkanfi. 2018. “Apoptosis of Intestinal Epithelial Cells Restricts Clostridium Difficile Infection in a Model of Pseudomembranous Colitis.” Nature Communications 9.
APA
Saavedra, P. H. V., Huang, L., Ghazavi, F., Kourula, S., Vanden Berghe, T., Takahashi, N., Vandenabeele, P., et al. (2018). Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. NATURE COMMUNICATIONS, 9.
Vancouver
1.
Saavedra PHV, Huang L, Ghazavi F, Kourula S, Vanden Berghe T, Takahashi N, et al. Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. NATURE COMMUNICATIONS. 2018;9.
MLA
Saavedra, Pedro Henrique Viana et al. “Apoptosis of Intestinal Epithelial Cells Restricts Clostridium Difficile Infection in a Model of Pseudomembranous Colitis.” NATURE COMMUNICATIONS 9 (2018): n. pag. Print.
@article{8599172,
  abstract     = {Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. Additionally, TcdA and TcdB engage the Pyrin inflammasome in macrophages, but whether Pyrin modulates CDI pathophysiology is unknown. Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase-3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo.},
  articleno    = {4846},
  author       = {Saavedra, Pedro Henrique Viana and Huang, Linyan and Ghazavi, Farzaneh and Kourula, Stephanie and Vanden Berghe, Tom and Takahashi, Nozomi and Vandenabeele, Peter and Lamkanfi, Mohamed},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  language     = {eng},
  pages        = {10},
  title        = {Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis},
  url          = {http://dx.doi.org/10.1038/s41467-018-07386-5},
  volume       = {9},
  year         = {2018},
}

Altmetric
View in Altmetric
Web of Science
Times cited: