Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Saavedra, Pedro; Huang, Linyan; Ghazavi, Farzaneh; Kourula, Stephanie; Vanden Berghe, Tom; Takahashi, Nozomi; Vandenabeele, Peter; Lamkanfi, Mohamed
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 10
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07386-5
• Languages: English
• ISSNs: 2041-1723

Abstract

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 thatC. 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 restrictsC. difficile infection in vivo. The enterotoxins TcdA and TcdB induce cytotoxicity of epithelial cells duringClostridium difficile infection. Here the authors show that bacterial induced epithelial cell death occurs via activation of caspases 3 and 7, resulting in apoptotic cell death.