Phosphodiesterase delta governs the mechanical properties of erythrocytes infected with Plasmodium falciparum gametocytes

To persist in the blood circulation and to be available for mosquitoes, Plasmodium falciparum gametocytes modify the deformability and the permeability of their erythrocyte host via cyclic AMP (cAMP) signaling pathway. Cyclic nucleotide levels are tightly controlled by phosphodiesterases (PDE), however in Plasmodium these proteins are poorly characterized. Here, we characterize the P. falciparum phosphodiesterase delta (PfPDEδ) and we investigate its role in the cAMP signaling-mediated regulation of gametocyte-infected erythrocyte mechanical properties. Our results revealed that PfPDEδ is a dual-function enzyme capable of hydrolyzing both cAMP and cGMP, with a higher affinity for cAMP. We also show that PfPDEδ is the most expressed PDE in mature gametocytes and we propose that it is located in parasitophorous vacuole at the interface between the host cell and the parasite. We conclude that PfPDEδ is the master regulator of both the increase in deformability and the inhibition of channel activity in mature gametocyte stages, and may therefore play a crucial role in the persistence of mature gametocytes in the bloodstream.