Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

Con Dogovski, Stanley C. Xie, Gaetan Burgio, Jess Bridgford, Sachel Mok, James M. McCaw, Kesinee Chotivanich, Shannon Kenny, Nina Gnädig, Judith Straimer, Zbynek Bozdech, David A. Fidock, Julie A. Simpson, Arjen M. Dondorp, Simon Foote, Nectarios Klonis, Leann Tilley*

*Corresponding author for this work

Research output: Contribution to journalArticle

144 Citations (Scopus)
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Abstract

Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART resistance.

Original languageEnglish
Article numbere1002132
Pages (from-to)1-26
Number of pages26
JournalPLoS Biology
Volume13
Issue number4
DOIs
Publication statusPublished - 22 Apr 2015

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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    Dogovski, C., Xie, S. C., Burgio, G., Bridgford, J., Mok, S., McCaw, J. M., ... Tilley, L. (2015). Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance. PLoS Biology, 13(4), 1-26. [e1002132]. https://doi.org/10.1371/journal.pbio.1002132