Salmonella enterica is a gastrointestinal pathogen of both humans and animals, and a major contributor to the global foodborne disease burden. Non-Typhoidal serovars including S. Typhimurium infect the small intestine and underlying immune cells to cause gastroenteritis in humans, and can induce systemic disease if left unchecked in immunocompromised individuals. Infected phagocytes such as macrophages facilitate the immune response against Salmonella infection by activating programmed cell death mechanisms. Death of the host macrophage halts intracellular bacterial replication, and enables the extracellular release of inflammatory cytokines and danger signals. However, Salmonellae use two specialised Type III Secretion Systems (T3SSs) to introduce effector proteins directly into the host cell cytosol, thus manipulating the cellular environment to promote bacterial survival. As such, characterisation of novel effector protein functions is crucial to understanding the success of these pathogens.
Our research discovered that S. Typhimurium induces the degradation of cellular inhibitor of apoptosis protein 1 (cIAP1), an important host cell adaptor of inflammatory signalling and inhibitor of apoptotic cell death. We observed strong association between cIAP1 loss and increased cellular cytotoxicity, with corresponding caspase-8/-3 activation. Depletion of cIAP1 required functional Salmonella Pathogenicity Island 1 (SPI-1) T3SS effector translocation, and was not prevented by pan-caspase, proteasomal or lysosomal inhibitors. Anti-cIAP1 immunoblot detected a low molecular weight peptide following S. Typhimurium infection, suggesting that SPI-1 effector/s may cleave cIAP1 during infection. Current work combines molecular, in vitro and in vivo techniques to explore the cIAP cleavage mechanism and determine the responsible effector protein, with transfection screens suggesting several key candidates. This finding suggests a new role for Salmonella effector proteins in activating, rather than preventing, host cell death in macrophages, which we hypothesise may promote dissemination of the bacteria.