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- Title
Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance.
- Authors
Siddiqui, Faiza A.; Cabrera, Mynthia; Brashear, Awtum; Kemirembe, Karen; Zenglei Wang; Jun Miao; Liwang Cui; Meilian Wang; Yaming Cao; Thanat Chookajorn; Zhaoqing Yang; Gang Dong; Rosenthal, Philip J.; Wang, Meilian; Wang, Zenglei; Miao, Jun; Chookajorn, Thanat; Yang, Zhaoqing; Cao, Yaming; Dong, Gang
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>These results suggest that altered hemoglobin digestion due to FP2a mutations may contribute to artemisinin resistance.
- Subjects
PLASMODIUM falciparum; ARTEMISININ; GENETIC polymorphisms; HAPLOTYPES; PARASITE antigens; THERAPEUTICS
- Publication
Journal of Infectious Diseases, 2018, Vol 218, Issue 3, p434
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiy188