The Salmonella SPI-2 type three secretion switch

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Salmonella is a bacterial pathogen that causes many important diseases in man (including typhoid fever) and veterinary livestock. The bacteria replicate inside host cells, in a membrane-bound compartment called a vacuole. In order to replicate, bacteria must interfere with normal cellular processes. They accomplish this by assembling a needle-like structure on their cell surface, through which virulence proteins can be discharged across the vacuole membrane into the host cell. But before this happens, some other bacterial proteins pass through the needle and make a small hole or 'pore' in the vacuole membrane. During this time, virulence protein secretion is held in check by a specific 'safety catch', within the bacterial cell. We found recently that once the pore is assembled, the bacteria recognize the mild pH of the host cytoplasm and exploit it as a signal to trigger disassembly of the safety catch, which then allows virulence proteins to be delivered. This process is absolutely crucial for the bacteria, because if they cannot deliver these proteins they cannot replicate. Therefore the purpose of this proposal is to study, at a detailed molecular level, the way in which the safety catch responds to the pH signal. The approaches that we will take to tackle this question are well established in my laboratory, and the results may have potential applications in the design of vaccines against Salmonella and also for new antibiotics that interfere with the ability of the bacteria to respond to the pH signal.