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Title: Targeting the cell stress response of plasmodium falciparum to overcome artemisinin resistance
Authors: Dogovski, Con
Xie, Stanley C.
Burgio, Gaetan
Bridgford, Jess
Mok, Sachel
McCaw, James M.
Chotivanich, Kesinee
Kenny, Shannon
Gnädig, Nina
Straimer, Judith
Bozdech, Zbynek
Fidock, David A.
Simpson, Julie A.
Dondorp, Arjen M.
Foote, Simon
Klonis, Nectarios
Tilley, Leann
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2015
Source: Dogovski, C., Xie, S. C., Burgio, G., Bridgford, J., Mok, S., McCaw, J. M., et al. (2015). Targeting the cell stress response of plasmodium falciparum to overcome artemisinin resistance. PLOS biology, 13(4), e1002132-.
Series/Report no.: PLOS biology
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.
ISSN: 1545-7885
DOI: 10.1371/journal.pbio.1002132
Schools: School of Biological Sciences 
Rights: © 2015 Dogovski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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