<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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Abhisheka Bansal [verfasserIn] Alvaro Molina-Cruz [verfasserIn] Joseph Brzostowski [verfasserIn] Jianbing Mu [verfasserIn] Louis H. Miller [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	PfCDPK2 exflagellation female gametocyte male gametocyte mosquito

Übergeordnetes Werk:	In: mBio - American Society for Microbiology, 2010, 8(2017), 5
Übergeordnetes Werk:	volume:8 ; year:2017 ; number:5

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1128/mBio.01656-17

Katalog-ID:	DOAJ06333254X

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allfields	10.1128/mBio.01656-17 doi (DE-627)DOAJ06333254X (DE-599)DOAJ89de155c15524a2398e01559fe8041c3 DE-627 ger DE-627 rakwb eng QR1-502 Abhisheka Bansal verfasserin aut <italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology Alvaro Molina-Cruz verfasserin aut Joseph Brzostowski verfasserin aut Jianbing Mu verfasserin aut Louis H. Miller verfasserin aut In mBio American Society for Microbiology, 2010 8(2017), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:8 year:2017 number:5 https://doi.org/10.1128/mBio.01656-17 kostenfrei https://doaj.org/article/89de155c15524a2398e01559fe8041c3 kostenfrei https://journals.asm.org/doi/10.1128/mBio.01656-17 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2017 5
spelling	10.1128/mBio.01656-17 doi (DE-627)DOAJ06333254X (DE-599)DOAJ89de155c15524a2398e01559fe8041c3 DE-627 ger DE-627 rakwb eng QR1-502 Abhisheka Bansal verfasserin aut <italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology Alvaro Molina-Cruz verfasserin aut Joseph Brzostowski verfasserin aut Jianbing Mu verfasserin aut Louis H. Miller verfasserin aut In mBio American Society for Microbiology, 2010 8(2017), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:8 year:2017 number:5 https://doi.org/10.1128/mBio.01656-17 kostenfrei https://doaj.org/article/89de155c15524a2398e01559fe8041c3 kostenfrei https://journals.asm.org/doi/10.1128/mBio.01656-17 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2017 5
allfields_unstemmed	10.1128/mBio.01656-17 doi (DE-627)DOAJ06333254X (DE-599)DOAJ89de155c15524a2398e01559fe8041c3 DE-627 ger DE-627 rakwb eng QR1-502 Abhisheka Bansal verfasserin aut <italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology Alvaro Molina-Cruz verfasserin aut Joseph Brzostowski verfasserin aut Jianbing Mu verfasserin aut Louis H. Miller verfasserin aut In mBio American Society for Microbiology, 2010 8(2017), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:8 year:2017 number:5 https://doi.org/10.1128/mBio.01656-17 kostenfrei https://doaj.org/article/89de155c15524a2398e01559fe8041c3 kostenfrei https://journals.asm.org/doi/10.1128/mBio.01656-17 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2017 5
allfieldsGer	10.1128/mBio.01656-17 doi (DE-627)DOAJ06333254X (DE-599)DOAJ89de155c15524a2398e01559fe8041c3 DE-627 ger DE-627 rakwb eng QR1-502 Abhisheka Bansal verfasserin aut <italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology Alvaro Molina-Cruz verfasserin aut Joseph Brzostowski verfasserin aut Jianbing Mu verfasserin aut Louis H. Miller verfasserin aut In mBio American Society for Microbiology, 2010 8(2017), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:8 year:2017 number:5 https://doi.org/10.1128/mBio.01656-17 kostenfrei https://doaj.org/article/89de155c15524a2398e01559fe8041c3 kostenfrei https://journals.asm.org/doi/10.1128/mBio.01656-17 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2017 5
allfieldsSound	10.1128/mBio.01656-17 doi (DE-627)DOAJ06333254X (DE-599)DOAJ89de155c15524a2398e01559fe8041c3 DE-627 ger DE-627 rakwb eng QR1-502 Abhisheka Bansal verfasserin aut <italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. PfCDPK2 exflagellation female gametocyte male gametocyte mosquito Microbiology Alvaro Molina-Cruz verfasserin aut Joseph Brzostowski verfasserin aut Jianbing Mu verfasserin aut Louis H. Miller verfasserin aut In mBio American Society for Microbiology, 2010 8(2017), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:8 year:2017 number:5 https://doi.org/10.1128/mBio.01656-17 kostenfrei https://doaj.org/article/89de155c15524a2398e01559fe8041c3 kostenfrei https://journals.asm.org/doi/10.1128/mBio.01656-17 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2017 5
language	English
source	In mBio 8(2017), 5 volume:8 year:2017 number:5
sourceStr	In mBio 8(2017), 5 volume:8 year:2017 number:5
format_phy_str_mv	Article
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callnumber-first	Q - Science
author	Abhisheka Bansal
spellingShingle	Abhisheka Bansal misc QR1-502 misc PfCDPK2 misc exflagellation misc female gametocyte misc male gametocyte misc mosquito misc Microbiology <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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topic_title	QR1-502 <italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation PfCDPK2 exflagellation female gametocyte male gametocyte mosquito
topic	misc QR1-502 misc PfCDPK2 misc exflagellation misc female gametocyte misc male gametocyte misc mosquito misc Microbiology
topic_unstemmed	misc QR1-502 misc PfCDPK2 misc exflagellation misc female gametocyte misc male gametocyte misc mosquito misc Microbiology
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title	<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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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
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title_auth	<italic toggle="yes"<Plasmodium falciparum</italic< Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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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. 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