Targeting Host and Apicomplexan Isoprenoid Pathways

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DESCRIPTION (provided by applicant): Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Toxoplasma gondii is the causative agent of human toxoplasmosis, a systemic infection acquired mostly through contaminated water and vegetables, or uncooked meat. Tissue cyst formation occurs soon after infection and is responsible for lifelong infection in immunocompetent individuals. At least one-third of the World's population and about 22.5% of Americans are seropositive for toxoplasmosis, making it one of the most prevalent infections in the United States. T. gondii resides intracellularly within parasitophorous vacuoles, and reactivation and dissemination of infection to different organs may occur following immune suppression. Cryptosporidium parvum is responsible for significant disease burden among children in developing countries and it can result in chronic and life-threatening enteritis in AIDS patients. The present chemotherapy available against T. gondii chronic infection and cryptosporidiosis is not effective and new drugs are urgently needed to treat both infections. T. gondii lacks a mevalonate pathway for the synthesis of isoprenoid precursors but harbor a 1-deoxy-D- xylulose-5-phosphate (DOXP) pathway in its apicoplast. This pathway generates isopentenyl diphosphate (IPP) and dimethyallyl diphosphate (DMAPP), which are condensed by the action of a unique farnesyl diphosphate synthase (TgFPPS) into farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP). Our preliminary data have indicated that the DOXP pathway is essential for T. gondii survival in its host. Surprisingly, though, drugs acting on the mevalonate pathway, like statins, are active in vitro and in vivo against the parasite. These results indicate that the parasite needs to synthesize some isoprenoid precursors (IPP, DMAPP), while salvaging others (FPP, GGPP) from its host. We will exploit this to develop a double hit strategy. Remarkably the model suggests that Cryptosporidium parvum should be highly susceptible to this approach. PUBLIC HEALTH RELEVANCE: Our goal is to find ways of interfering with Toxoplasma gondii metabolic pathways as a strategy for controlling infections caused by this and similar parasites. We have identified that the isoprenoid pathway is essential for T. gondii. The parasite synthesizes isoprenoid intermediates and takes up some from its host. Based on our results, we propose a strategy of combining inhibitors of both host and parasite isoprenoid pathways. In the second phase of the project we will adapt this strategy to dormant stages of T. gondii, and to other parasites such as Cryptosporidium.