Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of host and parasite interactions provides one approach to new drug and vaccine development. Plasmodium falciparum causes the most virulent form of human malaria. To do this the parasite must secrete proteins that stimulate invasion of the erythrocyte which is critical to maintain blood stage infection. We have identified a novel phosphatase of the human malaria parasite P. falciparum that functions in parasite invasion of the erythrocyte and establishment of new vacuole. It is predicted to be active in mosquito stages, suggesting it may provide a target in transmission blocking as well. Further it is bacterial-like phosphatase present in all malarial species, suggesting that signaling via the phosphatase may be a conserved mechanism of infection that could be targeted to develop inhibitors as a new treatment for malaria. This is a new target and there are no compounds currently available for it and thus our studies will contribute to drugs that will be active agains parasites, which are otherwise resistant to other drugs and targets. Importantly, drugs against this phosphatase will be early 'acting'and thus rapidly reduce fever. Molecular, genetic tools using expression of recombinant protein and cell and animal analyses of this P.falciparum phosphatase will be used in conjunction with high throughput screening assays. These studies will be important for developing chemo prophylaxis directed against a brand new target in a major human pathogen.

Public Health Relevance

Plasmodium falciparum causes the most virulent form of human malaria. To do this the parasite must secrete proteins from specialized 'apical organelles'and invade the erythrocyte. However, other than adhering to the erythrocyte, the molecular functions of these proteins are unknown. We have identified a secretory, bacterial like phosphatase of the human malaria parasite P. falciparum, with specificity for protein phosphotyrosine and optimal function needing neutral pH and Mn+2. It localizes to the apical complex of invading merozoites, most likely in the 'micronene's and is delivered to the host-pathogen junction at invasion and the vacuole of newly formed rings. It is then released as the host membrane invaginates to form the nascent vacuole providing the first evidence that Plasmodium introduces its own signaling mechanisms to infect the host. This parasite phosphatase is present in all malarial species, suggesting that its signaling activities may be a conserved mechanism of host infection. Since it is a novel target and bacteria- like, we think it is possible to develop selective inhibitors of this phosphatase as to develop new treatments for both vivax and falciparum malaria.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-BST-F (50))
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Yao, Yong
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University of Notre Dame
Schools of Arts and Sciences
Notre Dame
United States
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