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

Autor: Saavedra PHV; Department of Internal Medicine, Ghent University, Ghent, B-9052, Belgium.; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium., Huang L; Department of Internal Medicine, Ghent University, Ghent, B-9052, Belgium.; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.; School of Medical Technology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Ghazavi F; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium., Kourula S; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium., Vanden Berghe T; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium., Takahashi N; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium., Vandenabeele P; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium., Lamkanfi M; Department of Internal Medicine, Ghent University, Ghent, B-9052, Belgium. mlamkanf@its.jnj.com.; VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium. mlamkanf@its.jnj.com.; Janssen Immunosciences, World Without Disease Accelerator, Janssen Pharmaceutica, Pharmaceutical Companies of Johnson & Johnson, Beerse, B-2340, Belgium. mlamkanf@its.jnj.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2018 Nov 19; Vol. 9 (1), pp. 4846. Date of Electronic Publication: 2018 Nov 19.
DOI: 10.1038/s41467-018-07386-5
Abstrakt: 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.
Databáze: MEDLINE
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