Poster Presentation Lorne Infection and Immunity 2014

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.  Activation of Fas leads to recruitment of Fas-associated protein with death domain (FADD) and caspase-8 to form the death-inducing signalling complex (DISC) and mediate apoptotic cell death.  Fas-FasL interactions are crucial in the maintenance of immune homeostasis; in particular by mediating paracrine apoptosis of CD8+ T cells to down-regulate immune responses.  Fas is also 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.

We have recently shown that that the intestinal pathogen, Enteropathogenic E. coli (EPEC) secretes an effector protein, NleB, which has N-acetylglucosamine transferase activity and which modifies the death domain of FADD to ablate FasL mediated caspase-8 activation.  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 is critical for the bacteria to establish fulminant disease. This colonization defect is not evident in LPR or GLD mice, which are deficient for Fas signalling, highlighting the specificity of the Fas/FADD-NleB interaction. This study aims to interrogate 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. In addition, we also investigate the role of other pathways which rely on death domain proteins, such as TNFa signalling, in C. rodentium infection.