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Book Summary:
The human malaria parasite Plasmodium falciparum infects and develops within erythrocytes. This stage of infection is responsible for all the symptoms and pathologies of disease. In the intraerythrocytic stage, the parasite extensively remodels the host cell, presumably by delivering parasite effectors during invasion and development. The ligands involved in modification of the erythrocyte remain poorly characterized mainly due to the lack of well-developed genetic approaches. Sequencing of parasite and human genomes make computation approaches ideal for the discovery of novel effectors. During parasite entry, proteins associated with host-derived detergent resistant membrane (DRM) rafts are selectively recruited into the newly formed vacuole, but parasite proteins that contribute to raft-based vacuole development are unknown. Using bioinformatics we show that the P. falciparum genome contains an orthologue of human band 7 stomatin, a molecule related to mammalian proteins that have been linked to the formation of DRM-based invaginations. We find that plasmodial stomatin (Pfstomatin) is an integral membrane protein concentrated at invasion-associated rhoptry organelles. Further, when the parasite invades erythrocytes, Pfstomatin is inserted into the cytosolic face of the newly formed vacuole. Pfstomatin associates with DRMs and may form oligomers, providing the first evidence that rhoptries of an apicomplexan parasite contain DRM rafts. Thus, like the mammalian proteins, Pfstomatin may associate with non-clathrin coated, DRM-enriched vacuoles. We propose a new model of invasion and vacuole formation involving DRM-based interactions of both host and parasite molecules. Immediately following vacuolar biogenesis and throughout intraerythrocytic development, the malaria parasites secrete proteins across the vacuolar membrane into the erythrocyte. Using discovery-based bioinformatics we identified an 11-amino acid signal required for the secretion of proteins from the parasite vacuole to the erythrocyte. Searching the P. falciparum database with this signal reveals over 350 candidate exported proteins and conservation of the signal across Plasmodium species. Functional studies indicated the predictive value of the signal and its role in targeting virulence proteins to the erythrocyte. Erythrocyte modification by the parasite may involve plasmodial heat shock proteins and be much more complex than previously realized. The parasite effectors involved in invasion and intraerythrocytic growth are targets for the development of novel anti-malarial therapies. |
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