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Title: Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance
Authors: 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
Bio21 Molecular Science and Biotechnology Institute
Australian National University
Macquarie University, Australian School of Advanced Medicine
Nanyang Technological University
University of Melbourne
Royal Children's Hospital, Melbourne
Mahidol University
Columbia University Medical Center
Nuffield Department of Clinical Medicine
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 22-Apr-2015
Citation: PLoS Biology. Vol.13, No.4 (2015)
Abstract: © 2015 Dogovski et al. 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: 15457885
Appears in Collections:Scopus 2011-2015

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