title: An epigenetic antimalarial resistance mechanism involving parasite genes linked to nutrient uptake.
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.
authors.affiliation: Laboratory of Malaria and Vector Research, Office of Cyber Infrastructure and Computational Biology, NIAID, National Institutes of Health, Bethesda, Maryland 20852, USA.
authors.forename: Paresh
authors.initials: P
authors.lastname: Sharma
authors.forename: Kurt
authors.initials: K
authors.lastname: Wollenberg
authors.forename: Morgan
authors.initials: M
authors.lastname: Sellers
authors.forename: Kayvan
authors.initials: K
authors.lastname: Zainabadi
authors.forename: Kevin
authors.initials: K
authors.lastname: Galinsky
authors.forename: Eli
authors.initials: E
authors.lastname: Moss
authors.forename: Wang
authors.initials: W
authors.lastname: Nguitragool
authors.forename: Daniel
authors.initials: D
authors.lastname: Neafsey
authors.forename: Sanjay A
authors.initials: SA
authors.lastname: Desai
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D017125:Genes, Protozoan; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009705:Nucleosides / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D017920:Antiporters; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D009705:Nucleosides; D015800:Protozoan Proteins; C004500:blasticidin S
keywords: Antimalarial Drug Resistance; DNA Transformation; Drug Resistance; Epigenetics; Gene Silencing; Host-pathogen Interactions; Malaria; Parasitology