Songane, MJP;
(2015)
Understanding Clostridium difficile-mediated inflammasome activation.
Doctoral thesis , UCL (University College London).
Abstract
Interleukin 1beta (IL-1β) is critically involved in neutrophil recruitment, the cell-type largely responsible for the epithelial tissue damage and necrosis seen in Clostridium difficile infected patients. It is now well established that C. difficile toxin A (TcdA) and B (TcdB) trigger activation of the inflammasome, an inflammatory complex responsible for IL-1β and IL-18 secretion as well as pyroptosis (a form of inflammatory cell death).C. difficile toxin-induced inflammasome activation is mediated by an innate immune receptor named NLRP3. Despite many advances, upstream signals that activate NLRP3 in response to C. difficile infection remain ill-defined. In addition, the potential role of C. difficile flagellin in modulating inflammasome activity is unknown. We studied host-pathogen in human macrophages following co-culture with C. difficile R20291 and 630Δerm wild-type strains, and their respective toxin and flagellin mutants. Herein, we report several novel findings: (a) TcdA, TcdB and binary toxin (CDT) were equipotent in activating inflammasome; (b) C. difficile induced endoplasmic reticulum (ER) stress leading to X-box binding protein (XBP-1) splicing and induction of C/EBP homologous protein (CHOP) transcription, events upstream of NLRP3 activation; (c) TNF receptor-associated protein (TRAP-1) and autophagy limited C. difficile-mediated inflammasome activation. C. difficile infection also caused mitochondrial damage and subsequent increase in intracellular reactive oxygen species (ROS). However, ROS only affected priming of inflammasome components but not NLRP3 activation, suggesting ER stress as a major trigger of bacterial driven inflammasome activation. Infection studies using flagellin mutants suggest that flagellin is required for adherence, TLR5 interaction, optimal activation of nuclear factor kappa B (NF-κB) signalling and IL-1β secretion.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Understanding Clostridium difficile-mediated inflammasome activation |
| Event: | University College London |
| Publisher version: | http://www.ucl.ac.uk/ |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1471479 |
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