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An Epigenetic Antimalarial Resistance Mechanism Involving Parasite Genes Linked to Nutrient Uptake

2013; Elsevier BV; Volume: 288; Issue: 27 Linguagem: Inglês

10.1074/jbc.m113.468371

1083-351X

Paresh Sharma, Kurt Wollenberg, Morgan M. Sellers, Kayvan Zainabadi, Kevin Galinsky, Eli L. Moss, Wang Nguitragool, Daniel E. Neafsey, Sanjay A. Desai,

HIV/AIDS drug development and treatment

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.Background: Malaria parasites acquire antimalarial resistance through incompletely understood mechanisms.Results: Resistance to blasticidin S results from reversible silencing of parasite clag genes through histone modifications without DNA level changes.Conclusion: Sophisticated epigenetic control of clag genes permits regulated control of nutrient and antimalarial transport at the host membrane.Significance: This resistance mechanism allows rapid parasite adaptation to environmental pressures and is worrisome for drug discovery efforts. 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. Background: Malaria parasites acquire antimalarial resistance through incompletely understood mechanisms. Results: Resistance to blasticidin S results from reversible silencing of parasite clag genes through histone modifications without DNA level changes. Conclusion: Sophisticated epigenetic control of clag genes permits regulated control of nutrient and antimalarial transport at the host membrane. Significance: This resistance mechanism allows rapid parasite adaptation to environmental pressures and is worrisome for drug discovery efforts.