TY - JOUR
T1 - Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance
AU - Siddiqui, Faiza A.
AU - Cabrera, Mynthia
AU - Wang, Meilian
AU - Brashear, Awtum
AU - Kemirembe, Karen
AU - Wang, Zenglei
AU - Miao, Jun
AU - Chookajorn, Thanat
AU - Yang, Zhaoqing
AU - Cao, Yaming
AU - Dong, Gang
AU - Rosenthal, Philip J.
AU - Cui, Liwang
N1 - Funding Information:
Financial support. This study was funded by grants (U19AI089672 and R01AI128940) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health and a grant (81761128017) from National Natural Science Foundation of China.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].
PY - 2018/7/2
Y1 - 2018/7/2
N2 - Background Falcipain-2a ([FP2a] PF3D7-1115700) is a Plasmodium falciparum cysteine protease and hemoglobinase. Functional FP2a is required for potent activity of artemisinin, and in vitro selection for artemisinin resistance selected for an FP2a nonsense mutation. Methods To investigate associations between FP2a polymorphisms and artemisinin resistance and to characterize the diversity of the enzyme in parasites from the China-Myanmar border, we sequenced the full-length FP2a gene in 140 P falciparum isolates collected during 2004-2011. Results The isolates were grouped into 8 different haplotype groups. Haplotype group I appeared in samples obtained after 2008, coinciding with implementation of artemisinin-based combination therapy in this region. In functional studies, compared with wild-type parasites, the FP2a haplotypes demonstrated increased ring survival, and all haplotype groups exhibited significantly reduced FP2a activity, with group I showing the slowest protease kinetics and reduced parasite fitness. Conclusions These results suggest that altered hemoglobin digestion due to FP2a mutations may contribute to artemisinin resistance.
AB - Background Falcipain-2a ([FP2a] PF3D7-1115700) is a Plasmodium falciparum cysteine protease and hemoglobinase. Functional FP2a is required for potent activity of artemisinin, and in vitro selection for artemisinin resistance selected for an FP2a nonsense mutation. Methods To investigate associations between FP2a polymorphisms and artemisinin resistance and to characterize the diversity of the enzyme in parasites from the China-Myanmar border, we sequenced the full-length FP2a gene in 140 P falciparum isolates collected during 2004-2011. Results The isolates were grouped into 8 different haplotype groups. Haplotype group I appeared in samples obtained after 2008, coinciding with implementation of artemisinin-based combination therapy in this region. In functional studies, compared with wild-type parasites, the FP2a haplotypes demonstrated increased ring survival, and all haplotype groups exhibited significantly reduced FP2a activity, with group I showing the slowest protease kinetics and reduced parasite fitness. Conclusions These results suggest that altered hemoglobin digestion due to FP2a mutations may contribute to artemisinin resistance.
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U2 - 10.1093/infdis/jiy188
DO - 10.1093/infdis/jiy188
M3 - Article
C2 - 29659945
AN - SCOPUS:85050817088
SN - 0022-1899
VL - 218
SP - 434
EP - 442
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 3
ER -
