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PLoS Biol. 2015 Apr 22;13(4):e1002132. doi: 10.1371/journal.pbio.1002132. eCollection 2015 Apr.

Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance.

Author information

1
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.
2
John Curtin School of Medical Research, the Australian National University, Canberra, Australian Capital Territory, Australia; Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia.
3
School of Biological Sciences, Nanyang Technological University, Singapore.
4
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia; Murdoch Childrens Research Institute, Royal Childrens Hospital, Victoria, Australia.
5
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
6
Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America.
7
Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America; Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.
8
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia.
9
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.
10
John Curtin School of Medical Research, the Australian National University, Canberra, Australian Capital Territory, Australia.

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.

PMID:
25901609
PMCID:
PMC4406523
DOI:
10.1371/journal.pbio.1002132
[Indexed for MEDLINE]
Free PMC Article

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