Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria

Plasmodium falciparum is transmitted from humans to Anophelesmosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration throughmicrosphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was minia-turized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (ca-lyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in mac-rophage-depleted mice. Markedmechanical retention (80 % to 90%) of mature gametocytes was obtained in microplates follow-ing exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1M). Ma-ture gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. A