Investigation of conserved proteins that regulate transmission of the malaria parasite and Toxoplasma gondii.

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The malaria parasite, Plasmodium, and Toxoplasma gondii are related protozoal parasites that infect ~1/2 of the global population and cause a massive burden of death and disease. Although they have evolved very different mechanisms to undergo transmission between their hosts, there may be conserved features in the molecular mechanism that regulate the development of the T. gondii cysts, that survive ingestion and passage through the gastro-intestinal tract, and the development of malaria parasite oocysts in the mosquito midgut. This project will investigate the role of conserved proteins that are essential for the development of these transmission forms, with the aim of identifying new targets of therapeutics that disrupt the parasite lifecycles. We have previously identified a family of large surface proteins, the Cysteine Repeat Modular Proteins (CRMPs), that are essential for Plasmodium sporozoite development and egress from the oocyst. This project will investigate the role of CRMPs in the experimentally-amenable T .gondii model during cyst development in vitro and during chronic infection in vivo. In parallel, high-throughput CRISPR genetic screens will be carried out in T. gondii cysts cultured in vitro to identify novel proteins which are essential for cyst development and parasite differentiation and egress. Candidate genes will be disrupted in Plasmodium and Toxoplasma and differentiation and cyst formation will be assessed using high-resolution microscopy, biochemical approaches and infection assays.