Host-parasite interactions in chronic infection

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Toxoplasma gondii is a highly prevalent parasite that infects ~1/3 of the human population and a wide range of animals. In both humans and animals, Toxoplasma establishes chronic infections, predominantly in the brain and muscles. Toxoplasma is one of the leading causes of abortion in sheep and so has an economic impact on the farming industry. Animal infections also create a reservoir for transmission to humans through ingestion of undercooked meat from infected livestock. Despite the chronic cyst being critical for transmission of this zoonotic pathogen, we understand little of how the cyst forms, persists and impacts its host.Toxoplasma is a master at subverting host cell processes for its own benefit, and secretes an array of proteins that promote its survival early in infection. The role of secreted proteins during the chronic stage of infection remains understudied, and we hypothesise that secreted factors are also crucial for long-term infection. The central nervous system and skeletal muscle are the predominant sites of chronic Toxoplasma infection where the parasite forms cysts within cells. Crucially, parasite conversion to the chronic stage occurs spontaneously at high levels in neuronal and muscle (myotube) cells. This project will apply high-throughput CRISPR screening to identify secreted parasite factors required for establishing chronic infection. Screening will be done in both fibroblasts, a widely used model, and chronic infection specific cell types (eg. neurons and myotubes). This will identify mechanisms that are conserved across cell-types as well as niche-specific adaptations. Proteins essential for chronic infection will be investigated further by determining protein localisations, verifying their role in parasite survival and identifying interaction partners. The project will identify requirements for the development of this undruggable parasite stage and further our understanding of host-parasite interactions. It combines training in parasitology, molecular biology, microscopy, and next-generation sequencing with the opportunity for training in bioinformatics.