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

Selina Bopp, Pamela Magistrado, Wesley Wong, Stephen F. Schaffner, Angana Mukherjee, Pharath Lim, Mehul Dhorda, Chanaki Amaratunga, Charles J. Woodrow, Elizabeth A. Ashley, Nicholas J. White, Arjen M. Dondorp, Rick M. Fairhurst, Frederic Ariey, Didier Menard, Dyann F. Wirth and Sarah K. Volkman ()
Additional contact information
Selina Bopp: Harvard T.H. Chan School of Public Health
Pamela Magistrado: Harvard T.H. Chan School of Public Health
Wesley Wong: Harvard T.H. Chan School of Public Health
Stephen F. Schaffner: Harvard T.H. Chan School of Public Health
Angana Mukherjee: Harvard T.H. Chan School of Public Health
Pharath Lim: National Institutes of Health
Mehul Dhorda: Worldwide Antimalarial Resistance Network
Chanaki Amaratunga: National Institutes of Health
Charles J. Woodrow: Mahidol-Oxford Tropical Medicine Research Unit
Elizabeth A. Ashley: Myanmar-Oxford Clinical Research Unit
Nicholas J. White: Mahidol-Oxford Tropical Medicine Research Unit
Arjen M. Dondorp: Mahidol-Oxford Tropical Medicine Research Unit
Rick M. Fairhurst: National Institutes of Health
Frederic Ariey: Cochin Hospital Paris Descartes University
Didier Menard: Biology of Host-Parasite Interactions Unit, Institut Pasteur
Dyann F. Wirth: Harvard T.H. Chan School of Public Health
Sarah K. Volkman: Harvard T.H. Chan School of Public Health

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04104-z

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