Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability

Abstract

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

The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites

“…chromatin organization and protein transport) or with unknown functions 8,27 . In addition, cAMP/PfPKA-dependent signalling has been implicated in the regulation of ion channel conductance and new permeability pathways (NPP) in asexual blood stage parasites 28 and gametocytes 29 as shown through the use of pharmacological approaches (PKA/PDE inhibitors, exogenous 8-Bromo-cAMP) and transgenic cell lines (deletion of PfPDEδ, overexpression of PfPKAr) 28,29 . Similar experiments identified a putative role for cAMP/PfPKA-dependent signalling in regulating gametocyte-infected erythrocyte deformability 30 .…”

Tadalafil impacts the mechanical properties of Plasmodium falciparum gametocyte-infected erythrocytes

“…Among the different strategies evolved by P. falciparum parasites to persist for such a long time in the peripheral blood, gametocytes modify the mechanical properties of their erythrocyte host. As observed in mature asexual stages [4][5][6], immature gametocytes increase the stiffness and the permeability of their host cell by exporting proteins to the erythrocyte membrane [7,8]. The increase in stiffness is linked to both the interaction of the parasite proteins STEVOR with one or several erythrocyte membrane skeleton proteins composing the ankyrin complex [9,10] and to the remodelling of lateral and vertical interactions within the erythrocyte skeleton [11].…”

“…The increase in permeability is due to the activation of the new permeability pathways (NPPs) in which the RhopH proteins play an important role [7,12]. However, unlike in asexual stages, these changes in erythrocyte membrane mechanical properties are reversible in sexual stages.…”

“…These observations led to the hypothesis that the important stiffness of the infected erythrocyte may contribute to sequestration of immature stages in the bone marrow parenchyma by mechanical retention, and then the switch in deformability of the infected cell may trigger release of mature stages 3 in blood circulation. In parallel, gametocytes also regulate the permeability of their host cell: NPPs are activated in stage I GIE at levels similar to that of trophozoites and then this activity declines along gametocyte maturation, leading to undetectable channel activity in stage V GIE comparable to that usually observed in uninfected erythrocytes [7]. The virtual absence of channel activity in mature stages may allow the infected erythrocyte to decrease its osmotic fragility and thus to persist longer in the blood circulation.…”

cGMP homeostasis in malaria parasites—The key to perceiving and integrating environmental changes during transmission to the mosquito

“…It remains unknown whether XA can diffuse through the red blood cell and the parasitophorous vacuole membranes. It was recently shown that P. falciparum gametocytes regulate infected erythrocyte permeability via the new permeability pathway (Bouyer et al, 2020). However, this activity declines along gametocyte maturation and it is also uncertain whether XA could further traverse the parasite plasma membrane to reach GCα.…”