Molecular characterisation of bacterium-macrophage interactions: immune evasion, host-specificity and therapeutic potential

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The early stages of bacterial infections represent a critical 'battle-ground' between bacteria and innate immune cells, the outcome of which often determines infection or clearance. Accordingly, bacterial pathogens have evolved numerous sophisticated mechanisms for counteracting phagocytic killing by neutrophils and macrophages. Staphylococcus aureus is a major global human and livestock pathogen associated with an array of diseases from skin infections and necrotising pneumonia in humans, mastitis in ruminants, to joint infections in chickens. Importantly, multi-drug resistant strains of S. aureus have emerged and disseminated globally in humans and animals, limiting the options for effective treatment. The identification of novel therapeutic targets to reduce our dependence on antibiotics is urgently required. S. aureus can produce an array of molecules which specifically target the innate immune response and we have recently identified and characterised the prototype of a family of toxins which bind to specific receptors on leucocytes to inhibit phagocytosis. The toxin has multiple distinct activities for lymphocyte and leucocyte cell types and is a virulence factor in in an experimental model of infection. We have now identified several related secreted proteins made by S. aureus strains pathogenic for different host species that interact with innate immune cells and likely contribute to survival in specific hosts. Using state-of-the-art techniques in an interdisciplinary project, the project will involve characterisation of the molecular interaction of the proteins with macrophages of human, bovine, porcine and chicken origin. In particular the host-specificity of the interactions and the differential response of the innate immune cells from different host species, will be examined. Furthermore, the role in pathogenesis of the proteins will be examined in appropriate models of infection. Overall, the project will provide new insights into the capacity of a major bacterial pathogen to avoid killing by phagocytes, and to establish infections in human and livestock host species. In addition, the potential for the bacterial proteins to be used as vaccine components or to represent targets for novel therapeutics, will be tested. The project is interdisciplinary , benefiting from supervision by leading bacterial pathogen and macrophage biologists, and the successful candidate will receive a broad training in immunology, bacterial pathogenesis and host-pathogen interactions. The Roslin Institute and the University of Edinburgh in general is an outstanding environment to carry out research into the molecular pathogenesis of infectious diseases with world-leading scientists, excellent support and training opportunities. There will also be the potential for short-term training internships in collaborating laboratories in Europe or the USA.