Plasmodium Sporozoites Motility and Cell Invasion

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DESCRIPTION: (provided by the applicant): Malaria infection is initiated when Plasmodium sporozoites, which are injected by Anopheles mosquitoes, invade hepatocytes of the vertebrate host. Plasmodium sporozoites actively invade host cells, and display gliding motility, both actions being powered by parasite microfilaments. The molecular mechanisms involved in motility and invasion are largely unknown but are thought to be related. We have shown previously that a sporozoite surface molecule, the thrombospondin-related anonymous protein (TRAP), is required for sporozoite gliding motility and infection of hepatocytes. The objective of this proposal is to apply biochemical, cell biological and genetic approaches to elucidate the functional role of TRAP in host cell invasion by Plasmodium berghei. Our working hypothesis is that TRAP acts as a molecular link between the parasite cortical microfilaments and the host cell surface thereby, enabling the parasite to move and invade its target cell. TRAP, which is a typical type-1 transmembrane protein, has a long extracellular region, which contains two adhesive domains, and a short cytoplasmic tail. Our preliminary results indicate that TRAP may mediate target cell invasion by engaging with host cell surface proteins through its adhesive domains. In addition, the cytoplasmic tail of TRAP may interact with components of the sporozoite cortical microfilament system, possibly a motor protein such as myosin. The goal of this proposal is to identify and characterize host and parasite proteins that interact with the adhesive domains as well as the cytoplasmic tail of TRAP. Identification of TRAP-interacting molecules in the parasite or the host cell will further our understanding of sporozoite motility and invasion and will provide the basis for developing new malaria vaccines and chemotherapeutic agents.