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

Nat Commun. 2018 Nov 19;9(1):4846. doi: 10.1038/s41467-018-07386-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology
  • Caspase 3 / genetics*
  • Caspase 3 / immunology
  • Caspase 7 / genetics*
  • Caspase 7 / immunology
  • Clostridioides difficile / growth & development
  • Clostridioides difficile / immunology*
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Enterocolitis, Pseudomembranous / genetics
  • Enterocolitis, Pseudomembranous / immunology*
  • Enterocolitis, Pseudomembranous / microbiology
  • Enterotoxins / genetics
  • Enterotoxins / immunology
  • Epithelial Cells / immunology*
  • Epithelial Cells / microbiology
  • Gene Expression Regulation
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate
  • Inflammasomes / genetics
  • Inflammasomes / immunology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Macrophages / immunology
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organoids / immunology
  • Organoids / microbiology
  • Pyrin / genetics
  • Pyrin / immunology
  • Signal Transduction

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • Enterotoxins
  • Inflammasomes
  • Mefv protein, mouse
  • Pyrin
  • tcdA protein, Clostridium difficile
  • toxB protein, Clostridium difficile
  • Casp3 protein, mouse
  • Casp7 protein, mouse
  • Caspase 3
  • Caspase 7