Salmonella subversion of GTPase signalling at the host cell membrane, a key aspect of pathogen infection

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Bacterial diseases have had an enormous influence on human society until revolutions in public health and antibiotic discovery established a golden era of health. They nevertheless continue to pose a major problem in both underdeveloped and developed countries, causing widespread suffering, death and economic damage. They now present an ominous threat as we change the environment e.g. industrialising the food chain, and as bacteria become more and more resistant to antibiotics.The infamous bacterial pathogen Salmonella causes food-borne diarrhoeal disease in countries like ours, and life-threatening illness in the developing world, especially among children and people with weakened immune systems. Following human ingestion, e.g. via meat or eggs, Salmonella forces its way into cells of the host intestine and provokes a host immune response which causes nausea, cramps, and diarrhoea. Salmonella is able to survive this immune response, and it multiplies rapidly, generating ever-stronger disease. To initiate host invasion Salmonella delivers into target intestinal cells a battery of 'effector' proteins, which hijack control of the host cell cytoskeleton and cell shape. Salmonella uses several ways to achieve this crucial step. Our laboratory has recently found a mechanism that requires two host cell 'molecular switches', named Arf1 and Rac1, to be turned on to cause Salmonella to be internalised. Salmonella directs its effector SopE to activate Rac1, while hijacking a comparable host protein, ARNO, to activate Arf1. We will apply cell biology and biochemical approaches to investigate precisely how SopE and ARNO cooperate, how Salmonella controls this process, and whether other important bacterial pathogens use the same or similar strategy to initiate disease. We will study the other pathways Salmonella uses to get inside cells, and how the host immune system responds to the changes driven by these bacterial intruders. The information gained will provide new insights into how bacteria exploit host cells, enhance understanding of key processes in our own cells, and may reveal new pathogen targets to combat infection.