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/Title (Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance.)
/Author (Dogovski, Con and Xie, Stanley C. and Burgio, Gaetan and Bridgford, Jess and Mok, Sachel and McCaw, James M. and Chotivanich, Kesinee and Kenny, Shannon and Gn{\\"{a}}dig, Nina and Straimer, Judith and Bozdech, Zbynek and Fidock, David A. and Simpson, Julie A. and Dondorp, Arjen M. and Foote, Simon and Klonis, Nectarios and Tilley, Leann)
/bibtex#2F__markedentry ([jamesm:6])
/Subject (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.)
/bibtex#2Fbibtexkey (Dogovski-PLoSBiol-2015)
/bibtex#2Fdoi (10.1371/journal.pbio.1002132)
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/bibtex#2Finstitution (Department of Biochemistry and Molecular Biology and ARC Centre of Excellence for Coherent X-ray Science, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.)
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/bibtex#2Ftimestamp (2015.04.23)
/bibtex#2Furl (http://dx.doi.org/10.1371/journal.pbio.1002132)
/bibtex#2Fvolume (13)
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bibtex/institution/Department of Biochemistry and Molecular Biology and ARC Centre of Excellence for Coherent X-ray Science, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.
bibtex/journal/PLoS Biol
bibtex/language/eng
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bibtex/pii/PBIOLOGY-D-14-03592
bibtex/pmid/25901609
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bibtex/url/http://dx.doi.org/10.1371/journal.pbio.1002132
bibtex/volume/13
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.
Con Dogovski
Stanley C. Xie
Gaetan Burgio
Jess Bridgford
Sachel Mok
James M. McCaw
Kesinee Chotivanich
Shannon Kenny
Nina Gn{\"{a}}dig
Judith Straimer
Zbynek Bozdech
David A. Fidock
Julie A. Simpson
Arjen M. Dondorp
Simon Foote
Nectarios Klonis
Leann Tilley
10.1371/journal.pbio.1002132
Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance.
2015-04
application/pdf
Article
Con Dogovski
Stanley C. Xie
Gaetan Burgio
Jess Bridgford
Sachel Mok
James M. McCaw
Kesinee Chotivanich
Shannon Kenny
Nina Gn{\"{a}}dig
Judith Straimer
Zbynek Bozdech
David A. Fidock
Julie A. Simpson
Arjen M. Dondorp
Simon Foote
Nectarios Klonis
Leann Tilley
Dogovski-PLoSBiol-2015
10.1371/journal.pbio.1002132
:Dogovski-PLoSBiol-2015.pdf:PDF
Department of Biochemistry and Molecular Biology and ARC Centre of Excellence for Coherent X-ray Science, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.
PLoS Biol
eng
epublish
Apr
4
jamesm
e1002132
PBIOLOGY-D-14-03592
25901609
2015.04.23
Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance.
http://dx.doi.org/10.1371/journal.pbio.1002132
13
2015
Article
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