Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes

Abstract

Summary: Plasmodium falciparum gametocytes infect mosquitoes and are responsible for malaria transmission. New interventions that block transmission could accelerate malaria elimination. Gametocytes develop within erythrocytes and activate protein export pathways that remodel the host cell. Plasmepsin V (PMV) is an aspartyl protease that is required for protein export in asexual parasites, but its function and essentiality in gametocytes has not been definitively proven, nor has PMV been assessed as a transmission-blocking drug target. Here, we show that PMV is expressed and can be inhibited specifically in P. falciparum stage I-II gametocytes. PMV inhibitors block processing and export of gametocyte effector proteins and inhibit development of stage II-V gametocytes. Gametocytogenesis in the presence of sublethal inhibitor concentrations results in stage V gametocytes that fail to infect mosquitoes. Therefore, PMV primes gametocyte effectors for export, which is essential for the development and fitness of gametocytes for transmission to mosquitoes. : Plasmodium falciparum gametocytes infect mosquitoes and are responsible for malaria transmission. Jennison et al. discover that the aspartyl protease plasmepsin V is essential for P. falciparum gametocyte development. The inhibition of plasmepsin V prevents P. falciparum infection of mosquitoes, validating this enzyme as a transmission-blocking drug target. Keywords: malaria, gametocyte, export, inhibitor, drug, PEXEL, effector protein, remodeling, sexual stage, transmission blocking