microneme protein, sporozoite invasion, malaria vaccine, malarial circumsporozoite proteins
Plasmodium enters the blood stream of a mammalian host via a bite by an infected Anopheles mosquito. Translocation to the liver and introduction into a hepatocyte is a critical step for infectivity of the malaria parasite. Entry of the parasite follows two distinct pathways: rupturing of the hepatocyte membrane by migration or by the adhesion, internalization, and formation of a vacuole within the hepatocyte (Silvie et. al., 2004b). Only the latter pathway is necessary for the differentiation and proliferation of the blood-stage pathogen.
My focus will be primarily on the interaction of cell-surface proteins between the hepatocyte and the parasite. There are two well-studied proteins secreted by apical micronemes (i.e. vesicles at the anterior tip of the protozoan which secrete enzymes for parasite entry): the circumsporozoite protein (CSP) and the thrombospodin-related adhesive protein (TRAP; Silvie et. al., 2004b). The exocytosis of CSP and TRAP from micronemes within the parasite is dependent on the transient increase of intracellular calcium. Once the micronemes are excreted, CSP and TRAP localize to the membrane of Plasmodium. This process exposes CSP and TRAP to interact with hepatocyte cell-surface proteins, thus allowing the internalization and infection of the parasite by an unknown mechanism. A parasitophorous vacuole (PV) is formed after internalization, which is required for the differentiation of the exoerythrocytic form (EEF; Silvie et. al., 2004b)....
...Based on evidence seen in HepG2 cells, I will test the efficacy of anti-AMA-1 mAb in mice to neutralize the infectivity of Plasmodium yoelii in primary hepatocyte cultures from wild-type mice. Previously, HepG2 cells were protected against Plasmodium infectivity with increasing concentrations of anti-AMA-1 mAb (Silvie et. al., 2004a).
Secondly, I will test the infectivity of P. yoelli on primary hepatocytes from mice preincubated with anti-AMA-1 mAb and treated 3 hours post sporozoite introduction. In the past, HepG2 cells were found susceptible to Plasmodium infection after this procedure (Silvie et. al., 2004a). . This study will further verify the necessity of the AMA-1 protein for sporozoite entry into hepatocytes and subsequent infection.
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