دورية
Plasmodium bergheiK13 Mutations Mediate In VivoArtemisinin Resistance That Is Reversed by Proteasome Inhibition
| العنوان: | Plasmodium bergheiK13 Mutations Mediate In VivoArtemisinin Resistance That Is Reversed by Proteasome Inhibition |
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| المؤلفون: | Simwela, Nelson V., Stokes, Barbara H., Aghabi, Dana, Bogyo, Matt, Fidock, David A., Waters, Andrew P. |
| المصدر: | mBio; December 2020, Vol. 11 Issue: 6 |
| مستخلص: | Recent successes in malaria control have been seriously threatened by the emergence of Plasmodium falciparumparasite resistance to the frontline artemisinin drugs in Southeast Asia. P. falciparumartemisinin resistance is associated with mutations in the parasite K13 protein, which associates with a delay in the time required to clear the parasites upon drug treatment. Gene editing technologies have been used to validate the role of several candidate K13 mutations in mediating P. falciparumartemisinin resistance in vitrounder laboratory conditions. Nonetheless, the causal role of these mutations under in vivoconditions has been a matter of debate. Here, we have used CRISPR/Cas9 gene editing to introduce K13 mutations associated with artemisinin resistance into the related rodent-infecting parasite, Plasmodium berghei. Phenotyping of these P. bergheiK13 mutant parasites provides evidence of their role in mediating artemisinin resistance in vivo, which supports in vitroartemisinin resistance observations. However, we were unable to introduce some of the P. falciparumK13 mutations (C580Y and I543T) into the corresponding amino acid residues, while other introduced mutations (M476I and R539T equivalents) carried pronounced fitness costs. Our study provides evidence of a clear causal role of K13 mutations in modulating susceptibility to artemisinins in vitroand in vivousing the well-characterized P. bergheimodel. We also show that inhibition of the P. bergheiproteasome offsets parasite resistance to artemisinins in these mutant lines. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 21612129 21507511 |
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| DOI: | 10.1128/mBio.02312-20 |