Virulence-Associated Secreted and Surface Exposed Bacterial Proteins

Both Salmonella and B. pseudomallei have evolved a complex protein secretion system termed type III to deliver bacterial effector proteins into host cells that then modulate host cellular functions. Salmonella possess at least two TTSS (type III secretion system), TTSS-1 and TTSS- 2, each secreting a specific subset of virulence-associated proteins. The Group has identified a number of the TTSS-1 secreted effector proteins. These effector proteins (termed Sops for Salmonella outer proteins) are key virulence factors required for Salmonella invasion and induction of fluid secretion and inflammatory responses. However, function, sites of action and the three-dimensional structure of most of these proteins are yet to be determined. Even less is known about type III secreted proteins from B. pseudomallei, but it is clear that they are important virulence factors. <P>

To reveal some understanding of what host cell functions are modulated during infection and how, we will attempt to identify the cellular targets of bacterial effector proteins. We will construct and use genetically defined mutants in association with our biologically relevant model systems to begin to examine the importance of gene products. To investigate the function of effector proteins without the interference of other factors, we will introduce and express individual candidate effector proteins inside host cells. This will allow us functional and morphological examination of the cellular responses elicited by the activities of each bacterial effector protein.<P>

We will also express different effector proteins as fusions with GST or other tags and purify them. The purified proteins will be used for biochemical and crystallisation studies in collaboration with other labs. <P>
Finally, we will assess the relevance of the data obtained in vitro by performing experimental infections using the appropriate specific mutants in relevant animal model systems and monitoring the responses elicited by such infections.