Host cell small GTPase regulation and subversion by the intracellular bacterial pathogen Salmonella. Salmonella enterica is an intracellular bacterial pathogen of global importance that causes severe diarrhoea in humans (~150 million infections annually). Salmonella infections are often acquired via the food chain and environment from farmed animals that are reservoirs of infection. This poses a considerable risk to human health while the typhoid-like disease caused by Salmonella in farmed animals represents a substantial welfare and economic problem. To establish intracellular infections, Salmonella deploy virulence ‘effector’ proteins into target intestinal host cells that hijack master regulators of cellular functions known as Ras family small GTPases (e.g. Rho, Arf and Rab GTPases). By manipulating Rho and Arf GTPases to trigger actin polymerisation Salmonella are able to remodel the host cell plasma membrane and trigger their own uptake into Salmonella-containing vacuoles (SCVs). Salmonella effectors interfere with Rab GTPases, which control vesicular transport pathways, to ensure that the pathogen counteracts the action of bacteriocidal lysosomes and can survive in SCVs. Investigating S.Typhi and S.Typhimurium subversion of small GTPase pathways will illuminate virulence mechanisms and uncover important new cell biology governing the actin cytoskeleton and membrane transport. The PhD student will investigate small GTPase pathways and their interaction with Salmonella by combining protein biochemistry and cell biology approaches. The project will exploit established biomedical technology engineered in the laboratory to replicate virulence pathways at defined model membranes in cell-free extracts using purified pathogen effectors and cellular signalling components. This will provide new molecular insight into the host-pathogen interaction that will be challenged during infection using a range of culture mammalian cells and bacterial pathogens.
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