Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes
Charlie Jennison,
Leonardo Lucantoni,
Matthew T. O’Neill,
Robyn McConville,
Sara M. Erickson,
Alan F. Cowman,
Brad E. Sleebs,
Vicky M. Avery,
Justin A. Boddey
Affiliations
Charlie Jennison
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia
Leonardo Lucantoni
Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, Australia
Matthew T. O’Neill
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia
Robyn McConville
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia
Sara M. Erickson
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia
Alan F. Cowman
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia
Brad E. Sleebs
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia
Vicky M. Avery
Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, Australia
Justin A. Boddey
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia; Corresponding author
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
