Malaria parasites utilize two essential plasma membrane fusogens for gamete fertilization

Cell fusion of female and male gametes is the climax of sexual reproduction. In many organisms, the Hapless 2 (HAP2) family of proteins play a critical role in gamete fusion. We find that Plasmodium falciparum , the causative agent of human malaria, expresses two HAP2 proteins: Pf HAP2 and Pf HAP2p. These proteins are present in stage V gametocytes and localize throughout the flagellum of male gametes. Gene deletion analysis and genetic crosses show that Pf HAP2 and Pf HAP2p individually are essential for male fertility and thereby, parasite transmission to the mosquito. Using a cell fusion assay, we demonstrate that Pf HAP2 and Pf HAP2p are both authentic plasma membrane fusogens. Our results establish nonredundant essential roles for Pf HAP2 and Pf HAP2p in mediating gamete fusion in Plasmodium and suggest avenues in the design of novel strategies to prevent malaria parasite transmission from humans to mosquitoes.