An epigenetic antimalarial resistance mechanism involving parasite genes linked to nutrient uptake.
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.
['Sharma|Paresh|P|', 'Wollenberg|Kurt|K|', 'Sellers|Morgan|M|', 'Zainabadi|Kayvan|K|', 'Galinsky|Kevin|K|', 'Moss|Eli|E|', 'Nguitragool|Wang|W|', 'Neafsey|Daniel|D|', 'Desai|Sanjay A|SA|']
D000962:Antimalarials D017920:Antiporters D015815:Cell Adhesion Molecules D004351:Drug Resistance D004791:Enzyme Inhibitors D044127:Epigenesis, Genetic D017125:Genes, Protozoan D006801:Humans D017136:Ion Transport D016778:Malaria, Falciparum D009705:Nucleosides D010963:Plasmodium falciparum D015800:Protozoan Proteins
Epigenetics Antimalarial Drug Resistance Drug Resistance DNA Transformation Gene Silencing Host-pathogen Interactions Malaria Parasitology