Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes
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. Plasmeps...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719315645 |
| _version_ | 1818451035734147072 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Charlie Jennison |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-14T21:00:48Z |
| format | Article |
| id | doaj.art-6043059db5da4594912be1fa76539835 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T21:00:48Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6043059db5da4594912be1fa765398352022-12-21T22:47:35ZengElsevierCell Reports2211-12472019-12-01291237963806.e4Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to MosquitoesCharlie Jennison0Leonardo Lucantoni1Matthew T. O’Neill2Robyn McConville3Sara M. Erickson4Alan F. Cowman5Brad E. Sleebs6Vicky M. Avery7Justin A. Boddey8The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, AustraliaDiscovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, AustraliaDiscovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, QLD, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia; Corresponding authorSummary: 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 blockinghttp://www.sciencedirect.com/science/article/pii/S2211124719315645 |
| spellingShingle | 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 Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes Cell Reports |
| title | Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes |
| title_full | Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes |
| title_fullStr | Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes |
| title_full_unstemmed | Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes |
| title_short | Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes |
| title_sort | inhibition of plasmepsin v activity blocks plasmodium falciparum gametocytogenesis and transmission to mosquitoes |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719315645 |
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