blood cell that has stiffened
after treatment
© 2015 Ramdani et al.
The erectile dysfunction drug sildenafil (Viagra) could prevent transmission of the malaria parasite, according to research published in PLOS Pathogens.
Investigators found that sildenafil increases the stiffness of erythrocytes infected by the parasite Plasmodium falciparum.
This allows the cells to be eliminated from the bloodstream and may therefore reduce transmission of the malaria parasite from humans to mosquitoes.
The investigators noted that P falciparum has a complex developmental cycle that is completed partly in humans and partly in mosquitoes. Treatments for malaria target the asexual forms of this parasite that cause symptoms, but not the sexual forms transmitted from a human to a mosquito.
Malaria eradication therefore necessitates new types of treatments against sexual forms of the parasite in order to block transmission and prevent dissemination of the disease.
The sexual forms of P falciparum develop in human erythrocytes sequestered in the bone marrow before they are released into the blood. They are then accessible to mosquitoes, which can ingest them when they bite.
Circulating erythrocytes are deformable, thus preventing their clearance via the spleen. And gametocyte-infected erythrocytes can easily pass through the spleen and persist for several days in the blood circulation.
With this in mind, Ghania Ramdani, of Université Paris Descartes in France, and colleagues sought to stiffen the infected erythrocytes so they would be removed from circulation.
The team found that the deformability of gametocyte-infected erythrocytes is regulated by a signaling pathway that involves cAMP. When cAMP molecules accumulate, an erythrocyte becomes stiffer. And cAMP is degraded by the enzyme phosphodiesterase, which promotes erythrocyte deformability.
Using an in vitro model reproducing filtration by the spleen, the investigators were able to identify several pharmacological agents that inhibit phosophodiesterases and can therefore increase the stiffness of infected erythrocytes.
One of these agents is sildenafil. The team showed that a standard dose of the drug had the potential to increase the stiffness of sexual forms of the parasite and therefore favor the elimination of infected erythrocytes from the circulation.
This discovery could lead to new ways to stop the spread of malaria, the investigators said. They believe that modifying the active substance in sildenafil to block its erectile effect, or testing similar agents devoid of this effect, could indeed result in a treatment to prevent transmission of the parasite from humans to mosquitoes.
