Oral Presentation BacPath 13: Molecular Analysis of Bacterial Pathogens Conference 2015

Fas signaling in immune defense against the intestinal pathogen, Citrobacter rodentium (#44)

Catherine Kennedy 1 , Jaclyn Pearson 1 , Lucille Rankin 2 , Sze Ying Ong 1 , Lisa Mielke 2 , Seth Masters 2 , Jo O’Donnell 2 , Tracy Putoczki 2 , Mattias Ernst 2 , Gabrielle Belz 2 , Elizabeth L. Hartland 2
  1. University of Melbourne, Parkville, VIC, Australia
  2. Walter and Eliza Hall Institute, Parkville, VIC, Australia

Fas receptor (CD95, TNFR6) is a member of the TNF receptor superfamily and is best characterized for its ability to induce extrinsic apoptosis upon ligation of its ligand, FasL. Following Fas activation, Fas-associated protein with death domain (FADD) and caspase-8 are recruited to the receptor to form the death-inducing signalling complex (DISC). Fas-FasL interactions are crucial in the maintenance of immune homeostasis; in particular by mediating paracrine apoptosis of CD8+ cytotoxic- T cells to down-regulate immune responses.
Recent work in our laboratory shows that the intestinal pathogen, Enteropathogenic E. coli (EPEC) secretes an effector protein, NleB, into epithelial cells which targets FADD and ablates FasL mediated caspase-8 activation. Fas is expressed on the basolateral surface of intestinal epithelial cells, however the purpose of Fas-FasL interactions (homeostatic or immune regulatory) in this cell type is not clear. Infection of C57BL/6 mice with the model organism Citrobacter rodentium, deficient in nleB, shows impaired colonization compared to wild-type C. rodentium, indicating that the inhibition of Fas signalling in the intestinal epithelium by NleB is critical for the bacteria to establish fulminant disease. Conversely, infection of Fas-lpr mice, which do not express Fas receptor, with wild-type C. rodentium leads to increased inflammation in the colonic mucosa, increased bacterial invasion of the crypts and higher diarrhea scores compared to symptoms observed in C57BL/6 mice, highlighting the importance of Fas-signalling in controlling C. rodentium infection. Significantly, infection of Fas-lpr mice with the nleB-deficient C. rodentium reverses the colonization defect seen in C57BL/6 mice, showing the specificity of the NleB-Fas signaling pathway (FADD) interactions.

This study interrogates the role of Fas signalling in controlling mucosal infections. In particular, we aim to clarify the key cell types which express Fas and FasL and interact with each other to control C. rodentium infection.