The long term objectives are to understand the functions of specialized membrane organelles of plasmodia and their interactions with the host.
The specific aims are to identify and characterize plasmodial membrane proteins which may be responsible for membrane traffic in parasitized erythrocytes and may modify the properties of host erythrocytes. These aspects of parasite biology are directly relevant to understanding intracellular membrane traffic in eucaryotes and to parasite survival in the host. In the asexual blood stages, plasmodium has a complex relationship with the host which is poorly understood at the biochemical level. The use of biochemical and molecular biological tools to analyze cellular parasite phenomena should elucidate relevant modes of host parasite interactions. In general, intracellular pathways of membrane traffic are conserved in cells. There is evidence for directed transport of plasmodial proteins to the infected erythrocyte membrane which results in the modification of the structure and functions of host membranes. Drawing analogies between subcellular structures and mechanisms of membrane function in other cells, the organization of membrane protein pathways in plasmodia may be investigated. The analogies are provided from functional or structural homologies of purified plasmodial polypeptides (often easily detectable at the nucleotide level) with well defined protein molecules involved in vacuolar transport. The in-vitro cultivation of Plasmodium falciparum permits these studies in human malaria. Relatively large amounts of parasites can be grown in the laboratory to generate adequate quantities of RNA, DNA and immunopurified radiolabelled proteins whose structure may be investigated by chemical and enzymatic methods to determine specific aspects of post translational modifications of the polypeptides. The use of specific antibodies to protein components enables the determination of intracellular location (by microscopy and subcellular fractionation) biosynthesis and turnover (by pulse chase of radiolabel combined with immunoprecipitations) of the polypeptides of interest. Essential to the biochemical analysis of parasite modifications of the host erythrocyte membrane function, is the establishment of cell free plasmodial protein synthesis and transport systems, which are hitherto unavailable. Again by comparisons with other eucaryotic models and the understanding of specific parasite metabolic requirements and subcellular fractionation techniques, it should be possible to establish these cell free systems.
|Lopez-Estrano, Carlos; Bhattacharjee, Souvik; Harrison, Travis et al. (2003) Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum-infected erythrocytes. Proc Natl Acad Sci U S A 100:12402-7|
|Haldar, Kasturi; Mohandas, Narla; Samuel, Benjamin U et al. (2002) Protein and lipid trafficking induced in erythrocytes infected by malaria parasites. Cell Microbiol 4:383-95|
|Cheresh, Paul; Harrison, Travis; Fujioka, Hisashi et al. (2002) Targeting the malarial plastid via the parasitophorous vacuole. J Biol Chem 277:16265-77|
|Akompong, Thomas; Kadekoppala, Madhusudan; Harrison, Travis et al. (2002) Trans expression of a Plasmodium falciparum histidine-rich protein II (HRPII) reveals sorting of soluble proteins in the periphery of the host erythrocyte and disrupts transport to the malarial food vacuole. J Biol Chem 277:28923-33|
|Haldar, K; Samuel, B U; Mohandas, N et al. (2001) Transport mechanisms in Plasmodium-infected erythrocytes: lipid rafts and a tubovesicular network. Int J Parasitol 31:1393-401|
|Kadekoppala, M; Cheresh, P; Catron, D et al. (2001) Rapid recombination among transfected plasmids, chimeric episome formation and trans gene expression in Plasmodium falciparum. Mol Biochem Parasitol 112:211-8|
|Kadekoppala, M; Kline, K; Akompong, T et al. (2000) Stable expression of a new chimeric fluorescent reporter in the human malaria parasite Plasmodium falciparum. Infect Immun 68:2328-32|
|Ming, M; VanWye, J; Janse, C J et al. (1999) Gene organization of rab6, a marker for the novel Golgi of Plasmodium. Mol Biochem Parasitol 100:217-22|
|Haldar, K (1998) Intracellular trafficking in Plasmodium-infected erythrocytes. Curr Opin Microbiol 1:466-71|
|VanWye, J D; Haldar, K (1997) Expression of green fluorescent protein in Plasmodium falciparum. Mol Biochem Parasitol 87:225-9|
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