<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation

ABSTRACT Drug development efforts have focused mostly on the asexual blood stages of the malaria parasite Plasmodium falciparum. Except for primaquine, which has its own limitations, there are no available drugs that target the transmission of the parasite to mosquitoes. Therefore, there is a need t...

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Autores principales:	Abhisheka Bansal, Alvaro Molina-Cruz, Joseph Brzostowski, Jianbing Mu, Louis H. Miller
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/89de155c15524a2398e01559fe8041c3
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spelling	oai:doaj.org-article:89de155c15524a2398e01559fe8041c32021-11-15T15:51:50Z<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation10.1128/mBio.01656-172150-7511https://doaj.org/article/89de155c15524a2398e01559fe8041c32017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01656-17https://doaj.org/toc/2150-7511ABSTRACT Drug development efforts have focused mostly on the asexual blood stages of the malaria parasite Plasmodium falciparum. Except for primaquine, which has its own limitations, there are no available drugs that target the transmission of the parasite to mosquitoes. Therefore, there is a need to validate new parasite proteins that can be targeted for blocking transmission. P. falciparum calcium-dependent protein kinases (PfCDPKs) play critical roles at various stages of the parasite life cycle and, importantly, are absent in the human host. These features mark them as attractive drug targets. In this study, using CRISPR/Cas9 we successfully knocked out PfCDPK2 from blood-stage parasites, which was previously thought to be an indispensable protein. The growth rate of the PfCDPK2 knockout (KO) parasites was similar to that of wild-type parasites, confirming that PfCDPK2 function is not essential for the asexual proliferation of the parasite in vitro. The mature male and female gametocytes of PfCDPK2 KO parasites become round after induction. However, they fail to infect female Anopheles stephensi mosquitoes due to a defect(s) in male gametocyte exflagellation and possibly in female gametes. IMPORTANCE Despite reductions in the number of deaths it causes, malaria continues to be a leading infectious disease of the developing world. For effective control and elimination of malaria, multiple stages of the parasite need to be targeted. One such stage includes the transmission of the parasite to mosquitoes. Here, we demonstrate the successful knockout of PfCDPK2, which was previously thought to be indispensable for parasite growth in red blood cells. The PfCDPK2 KO parasites are incapable of establishing an infection in mosquitoes. Therefore, our study suggests that targeting PfCDPK2 may be a good strategy to control malaria transmission in countries with high transmission. Moreover, molecular understanding of the signaling pathway of PfCDPK2 may provide additional targets for malaria control.Abhisheka BansalAlvaro Molina-CruzJoseph BrzostowskiJianbing MuLouis H. MillerAmerican Society for MicrobiologyarticlePfCDPK2exflagellationfemale gametocytemale gametocytemosquitoMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology QR1-502
spellingShingle	PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology QR1-502 Abhisheka Bansal Alvaro Molina-Cruz Joseph Brzostowski Jianbing Mu Louis H. Miller <italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
description	ABSTRACT Drug development efforts have focused mostly on the asexual blood stages of the malaria parasite Plasmodium falciparum. Except for primaquine, which has its own limitations, there are no available drugs that target the transmission of the parasite to mosquitoes. Therefore, there is a need to validate new parasite proteins that can be targeted for blocking transmission. P. falciparum calcium-dependent protein kinases (PfCDPKs) play critical roles at various stages of the parasite life cycle and, importantly, are absent in the human host. These features mark them as attractive drug targets. In this study, using CRISPR/Cas9 we successfully knocked out PfCDPK2 from blood-stage parasites, which was previously thought to be an indispensable protein. The growth rate of the PfCDPK2 knockout (KO) parasites was similar to that of wild-type parasites, confirming that PfCDPK2 function is not essential for the asexual proliferation of the parasite in vitro. The mature male and female gametocytes of PfCDPK2 KO parasites become round after induction. However, they fail to infect female Anopheles stephensi mosquitoes due to a defect(s) in male gametocyte exflagellation and possibly in female gametes. IMPORTANCE Despite reductions in the number of deaths it causes, malaria continues to be a leading infectious disease of the developing world. For effective control and elimination of malaria, multiple stages of the parasite need to be targeted. One such stage includes the transmission of the parasite to mosquitoes. Here, we demonstrate the successful knockout of PfCDPK2, which was previously thought to be indispensable for parasite growth in red blood cells. The PfCDPK2 KO parasites are incapable of establishing an infection in mosquitoes. Therefore, our study suggests that targeting PfCDPK2 may be a good strategy to control malaria transmission in countries with high transmission. Moreover, molecular understanding of the signaling pathway of PfCDPK2 may provide additional targets for malaria control.
format	article
author	Abhisheka Bansal Alvaro Molina-Cruz Joseph Brzostowski Jianbing Mu Louis H. Miller
author_facet	Abhisheka Bansal Alvaro Molina-Cruz Joseph Brzostowski Jianbing Mu Louis H. Miller
author_sort	Abhisheka Bansal
title	<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
title_short	<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
title_full	<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
title_fullStr	<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
title_full_unstemmed	<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
title_sort	<italic toggle="yes">plasmodium falciparum</italic> calcium-dependent protein kinase 2 is critical for male gametocyte exflagellation but not essential for asexual proliferation
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/89de155c15524a2398e01559fe8041c3
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<italic toggle="yes">Plasmodium falciparum</italic> Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation

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