Analysing antibacterial immunity from two sides: host versus pathogen

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Bacterial infections represent a major problem to human health; often causing life-threatening diseases and persistent infections that can require extensive treatment with antibiotics. Salmonella causes a range of disease in humans, from gastro-enteritis to typhoid fever and is also prevalent in animals such as cattle, which can have serious economic consequences as well as public health implications. Normally, upon infection, host cells respond to bacterial products, activating a cascade of events that culminate in the production of molecules that trigger a robust immune defence programme to inactivate the bacteria. Many bacteria, including Salmonella, manipulate these host responses by the action of so-called virulence factors, producing a complex interaction between the host immune response and the incoming pathogen. This project on the one hand aims to understand how bacterial virulence factors produced and transported into host cells alter the outcome of infection to the advantage of the pathogen. We have identified several virulence factors that modulate host cell responses and we will now characterise their mechanism of action in detail. Deciphering how these virulence factors influence immune signalling cascades during infection provides valuable insight into what makes the bacteria pathogenic, provides important information on host processes that are targeted by the pathogen and is likely to provide valuable information for vaccine design and novel therapeutics. To complement this, research efforts are required to understand in molecular detail novel host mechanisms that restrict bacterial pathogens. Therefore, this project will also investigate the role of a family of host molecules (a group of proteins) that are called TRIMs. Research efforts have focused on TRIM function during viral infection but few have been studied in detail and the family remains poorly characterised during bacterial infection. Despite this, several lines of evidence suggest they have important functions upon host infection with bacteria. Therefore, I shall study how this group of proteins responds to bacterial infection and determine whether they can restrict the growth of bacteria within cells. These findings will reveal new functions for these proteins, many of which when mutated cause disease. Ultimately, with the improved understanding of host immune responses we are better informed on the best methods to combat bacterial infection. This is an important consideration given the rapidly developing rise in antibiotic resistant bacterial species.