An Epigenetic Antimalarial Resistance Mechanism Involving Parasite Genes Linked to Nutrient Uptake |
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Authors: | Paresh Sharma Kurt Wollenberg Morgan Sellers Kayvan Zainabadi Kevin Galinsky Eli Moss Wang Nguitragool Daniel Neafsey Sanjay A. Desai |
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Affiliation: | From the ‡Laboratory of Malaria and Vector Research and ;§Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, National Institutes of Health, Bethesda, Maryland 20852 and ;the ¶Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 |
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Abstract: | Acquired antimalarial drug resistance produces treatment failures and has led to periods of global disease resurgence. In Plasmodium falciparum, resistance is known to arise through genome-level changes such as mutations and gene duplications. We now report an epigenetic resistance mechanism involving genes responsible for the plasmodial surface anion channel, a nutrient channel that also transports ions and antimalarial compounds at the host erythrocyte membrane. Two blasticidin S-resistant lines exhibited markedly reduced expression of clag genes linked to channel activity, but had no genome-level changes. Silencing aborted production of the channel protein and was directly responsible for reduced uptake. Silencing affected clag paralogs on two chromosomes and was mediated by specific histone modifications, allowing a rapidly reversible drug resistance phenotype advantageous to the parasite. These findings implicate a novel epigenetic resistance mechanism that involves reduced host cell uptake and is a worrisome liability for water-soluble antimalarial drugs. |
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Keywords: | DNA Transformation Drug Resistance Gene Silencing Malaria Parasitology Antimalarial Drug Resistance Epigenetics Host-pathogen Interactions |
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