Scientists have identified the mechanisms by which the bacterial pathogen Clostridium difficile kills intestinal epithelial cells (IECs), thus destroying the protective mucosal barrier of the intestinal tract. Their findings are published in Nature Communications.
The bacterial Gram-positive pathogen C. difficile is a major healthcare-associated infection that can cause pseudomembranous colitis in patients following antibiotic treatment. It is the main contributor of gastroenteritis-associated deaths in the US and Europe. The bacterium produces two secreted toxins that induce a cytotoxic response in IECs that form the protective mucosal barrier of the intestinal tract.
It was known already that C. difficile exotoxins induce an inflammatory type of cell death termed pyroptosis in immune cells via activation of the pyrin inflammasome. However, C. difficile primarily targets IECs during infection, and the mechanism by which C. difficle kills IECs was unknown.
"By systematically deleting key genes involved in cell death processes in IECs, our work clarifies that—unlike in myeloid cells that undergo pyroptosis—C. difficile exotoxins induce apoptosis in IECs,” says first author Dr. Pedro Saavedra of VIB-UGent. “Following this basal observation, we were left with two main questions: how did the same toxins mediate distinct cell death modes in a cell type–dependent context, and what is the physiological impact of IEC apoptosis during infection?"
In fact, the scientists discovered that pyrin, a key immune sensor that triggers fast induction of pyroptosis in myeloid cells upon C. difficile infection, is not expressed in IECs, thus prioritizing the slower apoptosis process as the default cell death response in IECs.
"In vivo infection studies revealed that IEC apoptosis protects the host against C. difficile infection. This result was initially very surprising to us, as we expected that preventing cell death would protect the host from the detrimental outcome of intestinal epithelium damage,” says Saavedra. “Although our results demonstrated unequivocally that the gut epithelium undergoes apoptosis as a defensive response to C. difficile infection or exposure to the exotoxins, there are still major questions open. By tackling and understanding these basic processes, the team hopes to pave the way for the development of therapeutic strategies that broadly target gastrointestinal pathogens such as C. difficile by enhancing the host's defensive responses."