S-12 : Death receptors and bacterial diarrhoea

Abstract

Many bacterial pathogens have evolved distinct ways of disarming the inflammatory response and prolonging infection. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) interfere with the immune response by injecting virulence effector proteins into the host cell that shut down innate immune signalling pathways. We have identified effector proteins that prevent the activation of death receptor signalling. We recently discovered that NleB1 from EPEC binds to host cell death domain containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death receptor induced apoptosis. This inhibition depended on the N-GlcNAc transferase activity of NleB1, which specifically modified Arg117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing (A/E) pathogens antagonise death receptor induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.