Deciphering the role of secreted proteins at the host-parasite interface during chronic Toxoplasma gondii infection

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Toxoplasma gondii is a highly prevalent parasite that infects around 1/3 of the human population, as well as any warm-blooded animal. It establishes long-term chronic infection, predominantly in the muscles and the brain. If the immune system is weakened, for example in AIDs patients or during cancer treatment, these parasites can reactivate and cause disease. The chronic stage parasites are currently untreatable, and we understand little of how they establish long-term infection and what impact this has on the brain and mental health.Early in infection, the parasite invades cells and grows rapidly inside them. To do so, they secrete numerous proteins to take control of the cell, for example, by preventing that cell from killing them. To set up a chronic infection, the parasite converts to a slow-growing form and builds a protective wall forming a 'cyst'. This cyst lives within neurons in the brain, but it is not clear how this chronic form takes control of the host cell and protects itself against attack from the immune system. This research will investigate how the chronic stage parasite forms the cyst and defends itself to allow long-term infection.To understand more about how the parasite is manipulating the infected cell, I will determine which secreted proteins are important in chronic infection. I will use a powerful approach to generate pools of parasite mutants, where each parasite has a different gene disrupted. By using pools of parasite mutants and determining which parasites are able to survive, we can identify whether a gene is important or not. I will use this method to determine which genes are required for the parasite to form the chronic cyst. I will investigate the products of these genes - the proteins - investigating how they are important for chronic infection, for example, whether they are required to form the protective cyst wall, or if they help defend the cyst from the host. By looking at where these proteins localise, and what host proteins they interact with, I will identify pathways that the parasite needs to control to set up long-term infection. This will uncover the requirements and vulnerabilities of the chronic parasite, identifying new ways to target the parasite, and furthering our understanding of chronic infections.