Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum

被引：77
作者：
Bopp, Selina [1 ]
Magistrado, Pamela [1 ]
Wong, Wesley [1 ]
Schaffner, Stephen F. [1 ,2 ]
Mukherjee, Angana [1 ]
Lim, Pharath [3 ]
Dhorda, Mehul [4 ,5 ,6 ]
Amaratunga, Chanaki [3 ]
Woodrow, Charles J. [5 ]
Ashley, Elizabeth A. [6 ,7 ]
White, Nicholas J. [5 ,7 ]
Dondorp, Arjen M. [5 ,7 ]
Fairhurst, Rick M. [3 ]
Ariey, Frederic [8 ]
Menard, Didier [9 ,10 ,11 ]
Wirth, Dyann F. [1 ,2 ]
Volkman, Sarah K. [1 ,2 ,12 ]
机构：
[1] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA
[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA
[3] NIH, Rockville, MD 20892 USA
[4] Worldwide Antimalarial Resistance Network, Bangkok 10400, Thailand
[5] Mahidol Oxford Trop Med Res Unit, Bangkok 10400, Thailand
[6] Myanmar Oxford Clin Res Unit, Yangon, Myanmar
[7] Univ Oxford, Ctr Trop Med & Global Hlth, Oxford OX3 7FZ, England
[8] Paris Descartes Univ, Cochin Hosp, Parasitol Mycol Unit, Inst Cochin,INSERM,U1016, F-75014 Paris, France
[9] Inst Pasteur, Biol Host Parasite Interact Unit, F-75015 Paris, France
[10] CNRS, ERL 9195, F-75794 Paris, France
[11] INSERM, Unit U1201, F-75015 Paris, France
[12] Simmons Coll, Boston, MA 02115 USA
来源：
NATURE COMMUNICATIONS | 2018年 / 9卷
基金：
美国国家卫生研究院;
关键词：
DIHYDROARTEMISININ-PIPERAQUINE; IN-VITRO; WESTERN CAMBODIA; ARTEMISININ RESISTANCE; ANTIMALARIAL-DRUGS; MALARIA; ASSOCIATION; SUSCEPTIBILITY; MEFLOQUINE; PARASITES;
D O I：
10.1038/s41467-018-04104-z
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Multidrug resistant Plasmodium falciparum in Southeast Asia endangers regional malaria elimination and threatens to spread to other malaria endemic areas. Understanding mechanisms of piperaquine (PPQ) resistance is crucial for tracking its emergence and spread, and to develop effective strategies for overcoming it. Here we analyze a mechanism of PPQ resistance in Cambodian parasites. Isolates exhibit a bimodal dose-response curve when exposed to PPQ, with the area under the curve quantifying their survival in vitro. Increased copy number for plasmepsin II and plasmepsin III appears to explain enhanced survival when exposed to PPQ in most, but not all cases. A panel of isogenic subclones reinforces the importance of plasmepsin II-III copy number to enhanced PPQ survival. We conjecture that factors producing increased parasite survival under PPQ exposure in vitro may drive clinical PPQ failures in the field.
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页数：10
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