Salmonella enterica serovar Typhimurium is a common cause of gastroenteritis in humans and can cause a systemic typhoid-like disease in mice. Essential for pathogenesis are two Type Three Secretion Sytems (TTSS), encoded on Salmonella Pathogenicity Islands SPI1 and SPI2 that are used to translocate bacterial effector proteins into the host cell. The SPI1 and SPI2 TTSSs are differentially expressed and perform distinct roles in pathogenesis. The SPI1 TTSS, which is induced extracellularly, translocates a number of effectors that co-operatively mediate invasion of non-phagocytic cells. One of these effectors, SopB/SigD, is an inositol phosphatase that is involved in uptake but also induces the activation of mammalian serine threonine kinase Akt/PKB. Thus wild type S. Typhimurium but not the sigD deletion mutant strain induces Akt phosphorylation and activation in infected host cells. The role of Akt activation in pathogenesis remains unclear, however, in cultured epithelial cells we found that it can prevent the onset of apoptosis. Wild type serovar Typhimurium, but not the sigD deletion mutant strain, can block the induction of apoptosis by camptothecin and this is associated with decreased activation of caspase 3. This may be important for the survival and replication of intracellular bacteria. In macrophages activation of Akt by Salmonella is more complex since lipopolysaccharide will activate the kinase in the absence of SigD. However, we have found that SopB/SigD, increased inducible nitric oxide synthase levels and nitric oxide production in macrophages. To better understand the mechanism of translocation of SigD and other SPI1 effectors we have also carried out a detailed analysis of SigD binding to its chaperone SigE. This work is being carried out in collaboration with Dr. Natalie Strynadka at the University of British Columbia in Canada.
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