Salmonella bacteria inject a cocktail of stealth proteins into human immune cells to disable the body’s alarm system. These bacteria survive and multiply inside macrophages—white blood cells designed to kill invaders—by hiding in a membrane-bound sac and pumping out virulence proteins that neutralise the host’s defences and scavenge nutrients. But several of these proteins do something else: they block the infected cell from sending out chemical distress signals that would rally other immune cells. Researchers know almost nothing about how these “anti-immune” proteins work. This project will identify the specific cellular molecules they target, using advanced techniques that can detect tiny molecular changes inside infected cells. This is fundamental science. It will uncover new mechanisms of both bacterial infection and host-cell biology, with potential relevance to other intracellular pathogens such as *Mycobacterium tuberculosis* or *Listeria*. A deeper understanding of how Salmonella disarms the immune system could also guide the design of more effective vaccines—something still urgently needed for typhoid and other bacterial diseases that kill hundreds of thousands of people each year.
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Salmonella species are important bacterial pathogens causing a variety of human diseases, such as gastroenteritis and typhoid fever. Salmonella can invade and grow inside the cells of its host, including specialised white blood cells (macrophages) whose function is to destroy potential pathogens. Having entered host cells, Salmonella resides within a membranous sac (vacuole), and transfers through it a large number of virulence proteins. We know that several of these proteins enable bacterial growth inside the vacuole by detoxifying host defences and by acquiring nutrients. However other proteins, about which we know very little, block the ability of host cells to send alarm signals to other cells to mount an immune response. The proposed research involves detailed investigations into the functions of these 'anti-immune' virulence proteins. A key objective is to identify the cellular 'targets' with which they must interact to interfere with the host. To do this we will take advantage of very powerful modern techniques and instruments that can detect very small changes in the very complex environment of the infected cell. Through this research we are likely to discover new processes of pathogen and host cell biology, which could have implications for other important pathogens that propagate within our cells. Our work is also likely to provide valuable information for designing vaccines, which are still needed to provide effective long-term protection against Salmonella and other bacterial pathogens.
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