Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability

To ensure the transport of nutrients necessary for their survival, Plasmodium falciparum parasites increase erythrocyte permeability to diverse solutes. These New Permeation Pathways (NPP) have been extensively characterized in the pathogenic asexual parasite stages, however the existence of NPP has never been investigated in gametocytes, the sexual stages responsible for transmission to mosquitoes. Here, we show that NPP are still active in erythrocytes infected with immature gametocytes and that this activity declines along gametocyte maturation. Our results indicate that NPP are regulated by cyclic AMP (cAMP) signaling cascade during sexual parasite stages, and that the decrease in cAMP levels in mature stages results in a slowdown of NPP activity. We also show that NPP facilitate the uptake of artemisinin derivatives and that phosphodiesterase (PDE) inhibitors can reactivate NPP and increase drug uptake in mature gametocyte-infected erythrocytes. These processes are predicted to play a key role in P. falciparum gametocyte biology and susceptibility to antimalarials.