As recently published in PLOS Biology: 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. The researchers 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). They 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. The researchers show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response, and 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. The researchers 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, and 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 they suggest alternative approaches for the direct measurement of viability.
The 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.
Source: PLOS Biology
Resistance to artemisinin antimalarials, some of the most effective antimalarial drugs, has emerged in Southeast Asia, jeopardizing malaria control. The researchers have undertaken a detailed study of artemisinin-sensitive and-resistant strains of Plasmodium falciparum, the parasite responsible for malaria, taken directly from the field in a region where resistance is developing. They compared these strains to lab strains engineered with either mutant or wild-type resistance alleles, and demonstrate that in sensitive P. falciparum, artemisinin induces growth retardation and accumulation of ubiquitinated proteins, indicating that the drugs activate the cellular stress response. Resistant parasites, on the other hand, exhibit reduced protein ubiquitination and delayed onset of cell death following drug exposure. The research shows that proteasome inhibitors strongly synergize artemisinin activity, offering a means of overcoming artemisinin resistance and the research presents a detailed model of parasite responses and have modelled in vivo clearance profiles. The data indicate that extending artemisinin treatment from the standard three-day treatment to a four-day treatment will clear resistant parasites, thus preserving the use of this critical therapy in areas experiencing artemisinin resistance.
Citation: Dogovski C, Xie SC, Burgio G, Bridgford J, Mok S, et al. (2015) Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance. PLoS Biol 13(4): e1002132. doi:10.1371/journal.pbio.1002132
Academic Editor: David S. Schneider, Stanford University, UNITED STATES
Received: October 13, 2014; Accepted: March 16, 2015; Published: April 22, 2015
Copyright: © 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
Data Availability: All primary data are available by contacting the corresponding author. The Excel spreadsheet used for the modelling has been provided as Supporting Information. The entire genomes for the four Pailin strains have been made available through the European Nucleotide Archive (ENA) database under the accession number PRJEB8074.
Funding: This work was supported by the National Health & Medical Research Council of Australia (Grant#541904), the Australia Research Council (Grants: CE0561787 & DP110100624), the Singapore National Medical Council (NMRC/1265/2010), and National Institutes of Health, USA (R01 AI109023, to DAF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: ARTs, artemisinins; ACTs, ART combination therapies; DHA, dihydroartemisinin; LD50, 50% lethal dose; p.i., post-invasion; QHS, qinghaosu; RBC, red blood cell; Vmin, minimum viability
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