K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates

By J. Straimer, Nina F. Gnädig, B. Witkowski, C. Amaratunga, V. Duru, A. Ramadani, Mélanie A. Dacheux, N. Khim, Lei Zhang, Stephen C. Lam and 7 more. Science, 2014

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Mechanisms propelling drug resistance If it were to spread, resistance to the drug artemisinin would seriously derail the recent gains of global malaria control programs (see the Perspective by Sibley). Mutations in a region called the K13-propeller are predictive for artemisinin resistance in Southeast Asia. Mok et al. looked at the patterns of gene expression in parasites isolated from more than 1000 patients sampled in Africa, Bangladesh, and the Mekong region. A range of mutations that alter protein repair pathways and the timing of the parasite's developmental cycle were only found in parasites from the Mekong region. Straimer et al. genetically engineered the K13 region of parasites obtained from recent clinical isolates. Mutations in this region were indeed responsible for the resistance phenotypes. Science, this issue p. 431, p. 428; see also p. 373 Resistance to the primary antimalarial drug lies in mutations in protein repair and developmental pathways. [Also see Perspective by Sibley] The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.

Subfields: Parasitology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/894805e7984e34d93fbc5753c5e3c28facdb189d

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Citations in the corpus

• Malaria: Biology and Disease. (2016, positive): “…conferred an increased resistance on specific parasite lines not only showing that this gene was involved in the slow clearance phenotype for artemisinin but also suggesting that it was a complex phenotype for which other genes made a contribution to the overall phenotype (Straimer et al., 2015).”