Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance

Faiza A. Siddiqui, Mynthia Cabrera, Meilian Wang, Awtum Brashear, Karen Kemirembe, Zenglei Wang, Jun Miao, Thanat Chookajorn, Zhaoqing Yang, Yaming Cao, Gang Dong, Philip J. Rosenthal, Liwang Cui

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)434-442
Number of pages9
JournalJournal of Infectious Diseases
Volume218
Issue number3
DOIs
StatePublished - Jul 2 2018

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Siddiqui, F. A., Cabrera, M., Wang, M., Brashear, A., Kemirembe, K., Wang, Z., Miao, J., Chookajorn, T., Yang, Z., Cao, Y., Dong, G., Rosenthal, P. J., & Cui, L. (2018). Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance. Journal of Infectious Diseases, 218(3), 434-442. https://doi.org/10.1093/infdis/jiy188