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Gabriele Pradel (2011-2017)

The egress of malaria gametocytes from the red blood cell following parasite transmission to the mosquito

Malaria parasites are obligate intracellular pathogens that replicate in human red blood cells harbored by a protective membrane-bound vacuole. In order to pass through sexual reproduction, the parasites have to leave the shelter of the enveloping erythrocyte. Sexual reproduction is initiated by the uptake of dormant sexual precursor cells, the intraerythrocytic gametocytes, by blood-feeding Anopheles mosquitoes. In the mosquito midgut, the gametocytes become activated by environmental stimuli signalling the change of host. Within less than 15 minutes following activation malaria parasites egress from the erythrocytes to form gametes. Erythrocyte egress is crucial for the parasite to undergo gametogenesis and to continue its life cycle in the mosquito. The underlying molecular mechanisms of erythrocyte egress by the gametocytes, however, are up to date not well understood. During the first funding period of the priority programme SPP1580 we showed that Plasmodium falciparum gametocytes egress from the erythrocyte via an inside-out mode, during which the parasitophorous vacuole membrane ruptures prior to the erythrocyte membrane. We demonstrated that parasite-derived dipeptidyl aminopeptidases are involved in the breakdown of the parasitophorous vacuole membrane in a SUB1/SERA5-independent pathway, while subsequently the plasmodial perforin-like protein PPLP2 permeates the erythrocyte membrane to prepare the erythrocyte for rupture. Gamete formation is further accompanied by drastic membrane rearrangements, including the relocation of components of the inner membrane complex to the plasma membrane. During the second funding period, we will continue our work on the molecular mechanisms of membrane ruptures during gametocyte egress. Our focus will lie on 1) the detailed biochemical and biophysical characterization of the mode of action of PPLP2 during erythrocyte membrane permeation and its possible interaction with other perforin molecules; 2) the functional studies on plasmodial proteases involved in the disruption of the vacuolar compartment and the destabilization of the erythrocyte cytoskeleton; and 3) investigating the involvement of plasmodial phospholipases during membrane disintegration. Techniques include in vitro protein-protein and enzyme assays, biophysical membrane-protein interaction studies and functional genetics in combination with confocal laser scanning and electron microscopy.



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