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Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes.
Jennison, Charlie; Lucantoni, Leonardo; O'Neill, Matthew T; McConville, Robyn; Erickson, Sara M; Cowman, Alan F; Sleebs, Brad E; Avery, Vicky M; Boddey, Justin A.
Affiliation
  • Jennison C; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
  • Lucantoni L; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, Australia.
  • O'Neill MT; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia.
  • McConville R; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
  • Erickson SM; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
  • Cowman AF; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
  • Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
  • Avery VM; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, Australia.
  • Boddey JA; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: boddey@wehi.edu.au.
Cell Rep ; 29(12): 3796-3806.e4, 2019 12 17.
Article in En | MEDLINE | ID: mdl-31851913
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Plasmodium falciparum / Protozoan Proteins / Aspartic Acid Endopeptidases / Malaria, Falciparum / Enzyme Inhibitors / Gametogenesis / Culicidae Limits: Animals / Humans Language: En Journal: Cell Rep Year: 2019 Document type: Article Affiliation country: Australia Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Plasmodium falciparum / Protozoan Proteins / Aspartic Acid Endopeptidases / Malaria, Falciparum / Enzyme Inhibitors / Gametogenesis / Culicidae Limits: Animals / Humans Language: En Journal: Cell Rep Year: 2019 Document type: Article Affiliation country: Australia Country of publication: United States