Abstract
Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites.
Highlights
Recent renewed emphasis on the eradication of malaria has highlighted the need for novel interventions to target the parasite during transmission from the human host to the mosquito
Malaria transmission is ensured by deformable mature gametocyte-infected erythrocytes being taken up when a mosquito bites
We have investigated the role of cAMP-signalling in modulating gametocyte-infected erythrocytes (GIE) mechanical properties. Using both genetic and pharmacological manipulation of cAMP signalling in conjunction with the microsphiltration method to assess the ability of GIE to circulate through inter-endothelial splenic slits, we show that a decrease in cAMP levels increases mature GIE deformability, and increasing cAMP levels increases GIE stiffness
Summary
Recent renewed emphasis on the eradication of malaria has highlighted the need for novel interventions to target the parasite during transmission from the human host to the mosquito. For Plasmodium falciparum, the causative agent of the most severe form of human malaria, gametocyte maturation requires about 10 days and is divided in five morphological stages [2] During this period, immature gametocyte-infected erythrocytes (GIE) sequester in internal organs such as bone marrow and spleen [3,4,5,6]. The switch in deformability is linked to the de-association of the parasite-derived STEVOR proteins from the infected erythrocyte membrane [9] These processes must be tightly controlled and signalling likely plays a regulatory role. Adenylate cyclase alpha (PfACα) is highly expressed in gametocytes [26], and PKA activity is reportedly higher in gametocyte-producing parasites compared to parasites defective in gametocyte production [27], suggesting a potential role for cAMP-signalling in sexual development
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