The long term objective of this proposal is to characterize transport pathways in Plasmodium-infected erythrocytes. During the erythrocytic cycle, parasites actively remodel the host cell cytosol and plasma membrane to meet their metabolic requirements and to insure their long term survival. The pathways and processes that maintain the complex host cell-parasite relationship are poorly understood at the biochemical level. There is evidence that blood-stage parasites internalize membrane impermeable molecules from the external medium through a pathway that bypasses the erythrocyte cytosol. The identification and characterization of this new pathway has stimulated investigators to pursue new areas in malaria research, including parasite transfection, antisense RNA and Chemotherapy using membrane-impermeable drugs. Characterization of essential transport pathways will provide the opportunity to design strategies to disrupt (or utilize) these processes to compromise parasite viability. Ribosome inactivating proteins from plants will be used to investigate macromolecular transport pathways and evaluated for their antimalarial efficacy. These proteins were selected since they are biochemically well characterized and produce specific antiviral and antitumor cytotoxicity in vitro. Cytotoxicity appears to be best in situations where the organisms/cells are rapidly replicating as would be the case for Plasmodium and other infectious diseases. The intraparasitic targets of ribotoxins and basis of cytotoxicity will be investigated. Effects on parasite protein and nucleic acid syntheses and DNA stability and replication will be investigated. Depending on their mode of action, combined with the known replication schemes of other pathogens, the results from these studies may reveal opportunities whereby ribotoxins may be applied for the treatment of malaria and other infectious diseases.
