1. Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of Plasmodium falciparum.
- Author
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Chen N, LaCrue AN, Teuscher F, Waters NC, Gatton ML, Kyle DE, and Cheng Q
- Subjects
- Acetyl-CoA Carboxylase antagonists & inhibitors, Acetyl-CoA Carboxylase genetics, Acetyl-CoA Carboxylase metabolism, Antimalarials pharmacology, Apicoplasts drug effects, Apicoplasts genetics, Apicoplasts metabolism, Artemisinins pharmacology, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) antagonists & inhibitors, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) genetics, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) metabolism, Enzyme Inhibitors pharmacology, Erythrocytes drug effects, Erythrocytes parasitology, Gene Expression Regulation, Humans, Life Cycle Stages drug effects, Metabolic Networks and Pathways drug effects, Metabolic Networks and Pathways genetics, Mitochondria drug effects, Mitochondria genetics, Mitochondria metabolism, Mitochondrial Proteins genetics, Plasmodium falciparum drug effects, Plasmodium falciparum genetics, Plasmodium falciparum growth & development, Protozoan Proteins genetics, Transcription, Genetic, Fatty Acids biosynthesis, Life Cycle Stages genetics, Mitochondrial Proteins metabolism, Plasmodium falciparum metabolism, Protozoan Proteins metabolism, Pyruvates metabolism
- Abstract
Artemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways in P. falciparum during dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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