Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt
In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (p...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Dyann F. Wirth [verfasserIn] |
|---|
| Format: |
Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
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| Schlagwörter: |
Plasmodium falciparum - drug effects Plasmodium falciparum - genetics |
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| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 37, Seite 11672-11677 |
|---|---|
| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:37 ; pages:11672-11677 |
| Links: |
Volltext |
|---|
| DOI / URN: |
10.1073/pnas.1507142112 |
|---|
| Katalog-ID: |
OLC1970284536 |
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| 520 | |a In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. | ||
| 540 | |a Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences | ||
| 650 | 4 | |a Plasmodium falciparum - drug effects | |
| 650 | 4 | |a Protozoan Proteins - genetics | |
| 650 | 4 | |a Malaria - drug therapy | |
| 650 | 4 | |a Quinolines - chemistry | |
| 650 | 4 | |a Plasmodium falciparum - genetics | |
| 650 | 4 | |a Chloroquine - therapeutic use | |
| 650 | 4 | |a Membrane Transport Proteins - genetics | |
| 650 | 4 | |a Drug Resistance - genetics | |
| 650 | 4 | |a Genomes | |
| 650 | 4 | |a Adaptation | |
| 650 | 4 | |a Parasites | |
| 650 | 4 | |a Malaria | |
| 650 | 4 | |a Mutation | |
| 650 | 4 | |a Drug resistance | |
| 650 | 4 | |a drug resistance | |
| 650 | 4 | |a Plasmodium falciparum | |
| 650 | 4 | |a PfCRT | |
| 650 | 4 | |a Biological Sciences | |
| 650 | 4 | |a evolution | |
| 650 | 4 | |a malaria | |
| 700 | 0 | |a Daniel E. Neafsey |4 oth | |
| 700 | 0 | |a Eli L. Moss |4 oth | |
| 700 | 0 | |a Eric Legrand |4 oth | |
| 700 | 0 | |a Jessica Casteras |4 oth | |
| 700 | 0 | |a Lise Musset |4 oth | |
| 700 | 0 | |a Satish K. Dhingra |4 oth | |
| 700 | 0 | |a Béatrice Volney |4 oth | |
| 700 | 0 | |a Stéphane Pelleau |4 oth | |
| 700 | 0 | |a David A. Fidock |4 oth | |
| 700 | 0 | |a Sarah K. Volkman |4 oth | |
| 700 | 0 | |a Stanislaw J. Gabryszewski |4 oth | |
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10.1073/pnas.1507142112 doi PQ20160211 (DE-627)OLC1970284536 (DE-599)GBVOLC1970284536 (PRQ)g2666-c7ba7c0b68bd67afbc54c53874ee4191fcad454033e2b6d22a77a8918a435d670 (KEY)0583363920150000112003711672adaptiveevolutionofmalariaparasitesinfrenchguianar DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Dyann F. Wirth verfasserin aut Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Plasmodium falciparum - drug effects Protozoan Proteins - genetics Malaria - drug therapy Quinolines - chemistry Plasmodium falciparum - genetics Chloroquine - therapeutic use Membrane Transport Proteins - genetics Drug Resistance - genetics Genomes Adaptation Parasites Malaria Mutation Drug resistance drug resistance Plasmodium falciparum PfCRT Biological Sciences evolution malaria Daniel E. Neafsey oth Eli L. Moss oth Eric Legrand oth Jessica Casteras oth Lise Musset oth Satish K. Dhingra oth Béatrice Volney oth Stéphane Pelleau oth David A. Fidock oth Sarah K. Volkman oth Stanislaw J. Gabryszewski oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 37, Seite 11672-11677 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:37 pages:11672-11677 http://dx.doi.org/10.1073/pnas.1507142112 Volltext http://www.pnas.org/content/112/37/11672.abstract http://www.ncbi.nlm.nih.gov/pubmed/26261345 http://search.proquest.com/docview/1714443008 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4577156&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 37 11672-11677 |
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10.1073/pnas.1507142112 doi PQ20160211 (DE-627)OLC1970284536 (DE-599)GBVOLC1970284536 (PRQ)g2666-c7ba7c0b68bd67afbc54c53874ee4191fcad454033e2b6d22a77a8918a435d670 (KEY)0583363920150000112003711672adaptiveevolutionofmalariaparasitesinfrenchguianar DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Dyann F. Wirth verfasserin aut Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Plasmodium falciparum - drug effects Protozoan Proteins - genetics Malaria - drug therapy Quinolines - chemistry Plasmodium falciparum - genetics Chloroquine - therapeutic use Membrane Transport Proteins - genetics Drug Resistance - genetics Genomes Adaptation Parasites Malaria Mutation Drug resistance drug resistance Plasmodium falciparum PfCRT Biological Sciences evolution malaria Daniel E. Neafsey oth Eli L. Moss oth Eric Legrand oth Jessica Casteras oth Lise Musset oth Satish K. Dhingra oth Béatrice Volney oth Stéphane Pelleau oth David A. Fidock oth Sarah K. Volkman oth Stanislaw J. Gabryszewski oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 37, Seite 11672-11677 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:37 pages:11672-11677 http://dx.doi.org/10.1073/pnas.1507142112 Volltext http://www.pnas.org/content/112/37/11672.abstract http://www.ncbi.nlm.nih.gov/pubmed/26261345 http://search.proquest.com/docview/1714443008 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4577156&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 37 11672-11677 |
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10.1073/pnas.1507142112 doi PQ20160211 (DE-627)OLC1970284536 (DE-599)GBVOLC1970284536 (PRQ)g2666-c7ba7c0b68bd67afbc54c53874ee4191fcad454033e2b6d22a77a8918a435d670 (KEY)0583363920150000112003711672adaptiveevolutionofmalariaparasitesinfrenchguianar DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Dyann F. Wirth verfasserin aut Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Plasmodium falciparum - drug effects Protozoan Proteins - genetics Malaria - drug therapy Quinolines - chemistry Plasmodium falciparum - genetics Chloroquine - therapeutic use Membrane Transport Proteins - genetics Drug Resistance - genetics Genomes Adaptation Parasites Malaria Mutation Drug resistance drug resistance Plasmodium falciparum PfCRT Biological Sciences evolution malaria Daniel E. Neafsey oth Eli L. Moss oth Eric Legrand oth Jessica Casteras oth Lise Musset oth Satish K. Dhingra oth Béatrice Volney oth Stéphane Pelleau oth David A. Fidock oth Sarah K. Volkman oth Stanislaw J. Gabryszewski oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 37, Seite 11672-11677 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:37 pages:11672-11677 http://dx.doi.org/10.1073/pnas.1507142112 Volltext http://www.pnas.org/content/112/37/11672.abstract http://www.ncbi.nlm.nih.gov/pubmed/26261345 http://search.proquest.com/docview/1714443008 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4577156&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 37 11672-11677 |
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10.1073/pnas.1507142112 doi PQ20160211 (DE-627)OLC1970284536 (DE-599)GBVOLC1970284536 (PRQ)g2666-c7ba7c0b68bd67afbc54c53874ee4191fcad454033e2b6d22a77a8918a435d670 (KEY)0583363920150000112003711672adaptiveevolutionofmalariaparasitesinfrenchguianar DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Dyann F. Wirth verfasserin aut Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Plasmodium falciparum - drug effects Protozoan Proteins - genetics Malaria - drug therapy Quinolines - chemistry Plasmodium falciparum - genetics Chloroquine - therapeutic use Membrane Transport Proteins - genetics Drug Resistance - genetics Genomes Adaptation Parasites Malaria Mutation Drug resistance drug resistance Plasmodium falciparum PfCRT Biological Sciences evolution malaria Daniel E. Neafsey oth Eli L. Moss oth Eric Legrand oth Jessica Casteras oth Lise Musset oth Satish K. Dhingra oth Béatrice Volney oth Stéphane Pelleau oth David A. Fidock oth Sarah K. Volkman oth Stanislaw J. Gabryszewski oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 37, Seite 11672-11677 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:37 pages:11672-11677 http://dx.doi.org/10.1073/pnas.1507142112 Volltext http://www.pnas.org/content/112/37/11672.abstract http://www.ncbi.nlm.nih.gov/pubmed/26261345 http://search.proquest.com/docview/1714443008 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4577156&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 37 11672-11677 |
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10.1073/pnas.1507142112 doi PQ20160211 (DE-627)OLC1970284536 (DE-599)GBVOLC1970284536 (PRQ)g2666-c7ba7c0b68bd67afbc54c53874ee4191fcad454033e2b6d22a77a8918a435d670 (KEY)0583363920150000112003711672adaptiveevolutionofmalariaparasitesinfrenchguianar DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Dyann F. Wirth verfasserin aut Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Plasmodium falciparum - drug effects Protozoan Proteins - genetics Malaria - drug therapy Quinolines - chemistry Plasmodium falciparum - genetics Chloroquine - therapeutic use Membrane Transport Proteins - genetics Drug Resistance - genetics Genomes Adaptation Parasites Malaria Mutation Drug resistance drug resistance Plasmodium falciparum PfCRT Biological Sciences evolution malaria Daniel E. Neafsey oth Eli L. Moss oth Eric Legrand oth Jessica Casteras oth Lise Musset oth Satish K. Dhingra oth Béatrice Volney oth Stéphane Pelleau oth David A. Fidock oth Sarah K. Volkman oth Stanislaw J. Gabryszewski oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 37, Seite 11672-11677 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:37 pages:11672-11677 http://dx.doi.org/10.1073/pnas.1507142112 Volltext http://www.pnas.org/content/112/37/11672.abstract http://www.ncbi.nlm.nih.gov/pubmed/26261345 http://search.proquest.com/docview/1714443008 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4577156&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 37 11672-11677 |
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Dyann F. Wirth ddc 500 ddc 570 fid LING fid BIODIV misc Plasmodium falciparum - drug effects misc Protozoan Proteins - genetics misc Malaria - drug therapy misc Quinolines - chemistry misc Plasmodium falciparum - genetics misc Chloroquine - therapeutic use misc Membrane Transport Proteins - genetics misc Drug Resistance - genetics misc Genomes misc Adaptation misc Parasites misc Malaria misc Mutation misc Drug resistance misc drug resistance misc Plasmodium falciparum misc PfCRT misc Biological Sciences misc evolution misc malaria Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt |
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500 DNB 570 AVZ LING fid BIODIV fid Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt Plasmodium falciparum - drug effects Protozoan Proteins - genetics Malaria - drug therapy Quinolines - chemistry Plasmodium falciparum - genetics Chloroquine - therapeutic use Membrane Transport Proteins - genetics Drug Resistance - genetics Genomes Adaptation Parasites Malaria Mutation Drug resistance drug resistance Plasmodium falciparum PfCRT Biological Sciences evolution malaria |
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Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt |
| abstract |
In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. |
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In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. |
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In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. |
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Wirth</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2015</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.</subfield></datafield><datafield tag="540" ind1=" " ind2=" "><subfield code="a">Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Protozoan Proteins - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Malaria - drug therapy</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Quinolines - chemistry</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Chloroquine - therapeutic use</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Membrane Transport Proteins - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Drug Resistance - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genomes</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Adaptation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Parasites</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Malaria</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mutation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Drug resistance</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">drug resistance</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PfCRT</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Biological Sciences</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">evolution</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">malaria</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Daniel E. 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