Identifying The Machinery That Translocates Toxoplasma Effectors Into The Host Cell

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Abstract The major pathogenic species of Apicomplexa are all intracellular eukaryotic parasites that generally reproduce within a parasitophorous vacuole (PV) in infected host cells. This niche presents both an opportunity and a challenge to the parasites growing within – on the one hand, they are sequestered from some of the immune defenses that might detect their presence but at the same time, the PV membrane (PVM) presents a physical barrier to the export of protein effectors necessary to modulate host functions to the parasite's advantage. The phylum Apicomplexa includes many important human and animal pathogens including Plasmodium sp., the cause of human malaria, Cryptosporidium parvum, the cause of debilitating diarrheal disease, and Toxoplasma gondii, the cause of serious neurologic disease in the developing fetus and those who are immunocompromised through cancer (e.g., lymphoma), transplantation or infections, such as HIV-AIDS. We have recently determined that Toxoplasma tachyzoites have the ability to dramatically and specifically up-regulate expression of the human oncogene, c-Myc, using an effector released from dense granules, called GRA16. Using a genetic screen for mutants defective in c-Myc up-regulation, we have also recently identified the first components of the Toxoplasma machinery that translocates GRA16 and other dense granule effectors across the PVM. These novel proteins have been dubbed MYR1, MYR2 and MYR3. The goal of the work proposed here is to identify the complete or near complete machinery involved in translocation of effectors across the PVM, determine the host responses that are dependent on this machinery, and elucidate the importance of these effectors in Toxoplasma pathogenesis. We will do this through using a combination of biochemical and genetic approaches. Through this work, we will both unveil an important and novel piece of cell biology and identify crucial parasite components for eventual chemotherapeutic targeting and amelioration of the disease caused by this and related parasites.