gms | German Medical Science

The transmission of the malaria parasite Plasmodium falciparum from humans to mosquitoes is mediated by sexual precursor cells, the intraerythrocytic gametocytes, which become activated in the mosquito midgut by environmental stimuli and then undergo gametogenesis. Egress of the gametocytes from the enveloping erythrocyte is a crucial step for the parasites to prepare for fertilization, but the molecular mechanisms of gametocyte egress are not well understood. Previous studies indicated that plasmodial proteases are involved in this process [1], [2], but these proteases have not yet been identified. A new study showed that inhibition of the dipeptidyl aminopeptidases PfDPAP1 and PfDPAP3 resulted in blocked transmission of P. falciparum to the mosquito [3]. We now aimed to investigate, if the DPAPs play a role in gametocyte egress. We studied the effect of two DPAP-specific inhibitors (ML4118S and JCP410) on gametogenesis via exflagellation inhibition assay and electron microscopy. Both inhibitors were able to completely inhibit gametogenesis by impairing the rupture of the parasitophorous vacuole membrane. Noteworthy, while the asexual replication cycle DPAP3 activates the subtilisin-like protease PfSUB1, which in consequence processes the egress molecule PfSERA5 [4] these two proteins cannot be detected in gametocytes via immunofluorescence assays. Our data indicate that plasmodial DPAPs mediate the egress of the gametocytes from the enveloping erythrocyte in a PfSUB1/PfSERA5-independent pathway.