BIOLOGY AND IMMUNOLOGY OF MALARIA PARASITE LIVER-STAGES

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DESCRIPTION: Our knowledge of Plasmodium liver stage proteins remains largely 'a black box'. Convincing evidence exists that humans, non-human primates, and mice can be protected against sporozoite-induced malaria infection by immunization with irradiated sporozoites. Few studies of the liver-stage antigens of human malaria parasites have been carried out due to the lack of appropriate animal models and the limited supply of these antigens. To better understand the biology of the liver-stage malaria parasite and its role in protective immunity, we propose to analyze the parasite stage-specific gene expression during the transition from sporozoite to merozoite cycle in vitro and in vivo. To facilitate the analysis of EE-stage parasites, we will identify Plasmodium yoelii gene in the infected mouse liver, the expression of which is induced early after infection, and shut off during the blood-stage cycle. Differential display analysis will be utilized to identify parasite genes that are expressed in hepatocytes infected with -irradiated and non-irradiated sporozoites. Plasmodium liver-stage schizonts will be isolated by laser-capture micro dissection and the generation of liver-stage cDNA for library construction and micro array analysis. In addition, we will identify Plasmodium falciparum liver-stage specific genes that are selectively expressed in human hepatocytes in vitro and in vivo. Initially, the infected hepatocytes obtained from either hHGF/SCID and hHGF/RAG1 mice transplanted with human hepatocytes, or hepatocyte cultures, will be used to generate P. falciparum EE-stages. Finally, we will define the contribution of P. yoelii liver-stage gene products in protective immunity via DNA immunizations.