Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum
Identifieur interne : 001377 ( Main/Exploration ); précédent : 001376; suivant : 001378Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum
Auteurs : Long Cui [États-Unis] ; Zenglei Wang [États-Unis] ; Jun Miao [États-Unis] ; Miao Miao [États-Unis] ; Ramesh Chandra [États-Unis] ; Hongying Jiang [États-Unis] ; Xin-Zhuan Su [États-Unis] ; Liwang Cui [États-Unis]Source :
- Molecular Microbiology [ 0950-382X ] ; 2012-10.
English descriptors
- Teeft :
- Antimalarial, Antimalarial drugs, Antimicrob, Antimicrob agents chemother, Antioxidant, Antioxidant activities, Antioxidant activity, Antioxidant defence, Antioxidant defence system, Antioxidant pathways, Armd phenotype, Artemisinin, Artemisinin resistance, Artesunate, Asterisk, Biochem parasitol, Biweekly interval, Blackwell publishing, Candidate genes, Cellular levels, Chemother, Chloroquine, Chloroquine resistance, Clone, Copy number, Curcumin, Defence, Derivative, Dha1, Dha1 dha2, Dha2, Dha2 parasites, Downregulated gene pools, Drug pressure, Drug resistance, Drug selection, Falciparum, Falciparum malaria, Family drugs, Food vacuole, Gene, Gene expression, Genetic backgrounds, Genome, Ginsburg, Intracellular, Malaria, Malaria parasite plasmodium falciparum, Malaria parasites, Microarray, Microarray analysis, Microarray data, Microbiol, Microbiology, Molecular microbiology, Multiple antimalarial drugs, Mutation, Oxidative, Oxidative stress, Parasite, Parasite clearance, Parasite clones, Parasite lines, Parasite strains, Parasitemia, Parasitol, Partner drugs, Pathway, Pfatp6, Pfmdr1, Pfmdr1 copy number, Pfmdr1 copy numbers, Pfmdr1 expression, Pfmdr1 gene, Pfmdr1 mutations, Phenotype, Plasmodium, Plasmodium falciparum, Plasmodium protein, Proc natl acad, Quiescence mechanism, Recovery rates, Redox metabolism, Reselection, Resistance mechanism, Resistance mechanisms, Resistance phenotype, Respective parasite strains, Reversible changes, Revertant, Revertant parasites, Ring stage, Schizont, Schizont stages, Stable changes, Statistical analysis, Time points, Trophozoite, Upregulated, Upregulated genes, Upregulation, Witkowski.
Abstract
The recent reports of artemisinin (ART) resistance in the Thai–Cambodian border area raise a serious concern on the long‐term efficacy of ARTs. To elucidate the resistance mechanisms, we performed in vitro selection with dihydroartemisinin (DHA) and obtained two parasite clones from Dd2 with more than 25‐fold decrease in susceptibility to DHA. The DHA‐resistant clones were more tolerant of stressful growth conditions and more resistant to several commonly used antimalarial drugs than Dd2. The result is worrisome as many of the drugs are currently used as ART partners in malaria control. This study showed that the DHA resistance is not limited to ring stage, but also occurred in trophozoites and schizonts. Microarray and biochemical analyses revealed pfmdr1 amplification, elevation of the antioxidant defence network, and increased expression of many chaperones in the DHA‐resistant parasites. Without drug pressure, the DHA‐resistant parasites reverted to sensitivity in approximately 8 weeks, accompanied by de‐amplification of pfmdr1 and reduced antioxidant activities. The parallel decrease and increase in pfmdr1 copy number and antioxidant activity and the up and down of DHA sensitivity strongly suggest that pfmdr1 and antioxidant defence play a role in in vitro resistance to DHA, providing potential molecular markers for ART resistance.
Url:
DOI: 10.1111/j.1365-2958.2012.08180.x
Affiliations:
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microbiology</term><term>Multiple antimalarial drugs</term><term>Mutation</term><term>Oxidative</term><term>Oxidative stress</term><term>Parasite</term><term>Parasite clearance</term><term>Parasite clones</term><term>Parasite lines</term><term>Parasite strains</term><term>Parasitemia</term><term>Parasitol</term><term>Partner drugs</term><term>Pathway</term><term>Pfatp6</term><term>Pfmdr1</term><term>Pfmdr1 copy number</term><term>Pfmdr1 copy numbers</term><term>Pfmdr1 expression</term><term>Pfmdr1 gene</term><term>Pfmdr1 mutations</term><term>Phenotype</term><term>Plasmodium</term><term>Plasmodium falciparum</term><term>Plasmodium protein</term><term>Proc natl acad</term><term>Quiescence mechanism</term><term>Recovery rates</term><term>Redox metabolism</term><term>Reselection</term><term>Resistance mechanism</term><term>Resistance mechanisms</term><term>Resistance phenotype</term><term>Respective parasite strains</term><term>Reversible 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To elucidate the resistance mechanisms, we performed in vitro selection with dihydroartemisinin (DHA) and obtained two parasite clones from Dd2 with more than 25‐fold decrease in susceptibility to DHA. The DHA‐resistant clones were more tolerant of stressful growth conditions and more resistant to several commonly used antimalarial drugs than Dd2. The result is worrisome as many of the drugs are currently used as ART partners in malaria control. This study showed that the DHA resistance is not limited to ring stage, but also occurred in trophozoites and schizonts. Microarray and biochemical analyses revealed pfmdr1 amplification, elevation of the antioxidant defence network, and increased expression of many chaperones in the DHA‐resistant parasites. Without drug pressure, the DHA‐resistant parasites reverted to sensitivity in approximately 8 weeks, accompanied by de‐amplification of pfmdr1 and reduced antioxidant activities. The parallel decrease and increase in pfmdr1 copy number and antioxidant activity and the up and down of DHA sensitivity strongly suggest that pfmdr1 and antioxidant defence play a role in in vitro resistance to DHA, providing potential molecular markers for ART resistance.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li><li>Pennsylvanie</li></region><settlement><li>University Park (Pennsylvanie)</li></settlement><orgName><li>Université d'État de Pennsylvanie</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Cui, Long" sort="Cui, Long" uniqKey="Cui L" first="Long" last="Cui">Long Cui</name></region><name sortKey="Chandra, Ramesh" sort="Chandra, Ramesh" uniqKey="Chandra R" first="Ramesh" last="Chandra">Ramesh Chandra</name><name sortKey="Cui, Liwang" sort="Cui, Liwang" uniqKey="Cui L" first="Liwang" last="Cui">Liwang Cui</name><name sortKey="Cui, Liwang" sort="Cui, Liwang" uniqKey="Cui L" first="Liwang" last="Cui">Liwang Cui</name><name sortKey="Jiang, Hongying" sort="Jiang, Hongying" uniqKey="Jiang H" first="Hongying" last="Jiang">Hongying Jiang</name><name sortKey="Miao, Jun" sort="Miao, Jun" uniqKey="Miao J" first="Jun" last="Miao">Jun Miao</name><name sortKey="Miao, Miao" sort="Miao, Miao" uniqKey="Miao M" first="Miao" last="Miao">Miao Miao</name><name sortKey="Su, Xin Huan" sort="Su, Xin Huan" uniqKey="Su X" first="Xin-Zhuan" last="Su">Xin-Zhuan Su</name><name sortKey="Wang, Zenglei" sort="Wang, Zenglei" uniqKey="Wang Z" first="Zenglei" last="Wang">Zenglei Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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