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Signaling mechanisms involved in regulated vesicle discharge in Plasmodium falciparum

Abstract : The activation of Plasmodium falciparum gametocytes by exposure to low temperature and xanthurenic acid leads to the egress of mature male and female gametes from host erythrocytes, which is essential for fertilization and subsequent zygote formation. Gametes contain cytosolic vesicles bearing a pore forming protein known as PfPLP2. During egress, PfPLP2 containing vesicles gets redistributed from gamete cytoplasm to periphery. Subsequently, PfPLP2 is secreted from these vesicles leading to perforation of host erythrocyte membrane resulting in gamete egress. In this study, we have identified the role of a patatin-like phospholipase A2 (PfPATPL1) in P. falciparum gamete egress. We have taken a reverse genetics approach to generate a conditional knock down of PfPATPL1 by fusion to a destabilization domain (DD). We have knocked down PfPATPL1 in Stage V gametocytes by removal of Shield-1 ligand and found that PfPATPL1 is required during different steps of gametogenesis including gametocyte rounding up, gamete egress and male gamete exflagellation. We have also found that PfPATPL1 is needed for redistribution of PfPLP2 bearing vesicles to the gamete periphery during egress. Additionally, we have utilized a known inhibitor of phospholipase A2 known as 4- bromophenacyl bromide (4-BPB) to study the importance of PLA2 activity in gametogenesis. We have found that 4-BPB treatment also leads to defects in gametocyte rounding up, inhibits gamete egress and male gamete exflagellation. 4-BPB treatment also hampers the redistribution of PfPLP2 containing vesicles to gamete periphery. When the mosquitoes were fed with 4-BPB treated gametocytes in a standard membrane feeding assay (SMFA), we observed a significant decline in mosquito infection rate and a drastic drop in oocyst density and number of infected mosquitos. These data suggests that PfPATPL1 is important for gamete development in mosquitos and may serve as a promising target for transmmision intervention strategies.
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  • HAL Id : tel-02411562, version 2

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Pallavi Singh. Signaling mechanisms involved in regulated vesicle discharge in Plasmodium falciparum. Cellular Biology. Université Pierre et Marie Curie - Paris VI, 2017. English. ⟨NNT : 2017PA066345⟩. ⟨tel-02411562v2⟩

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