Epigenetic switches in clag3 genes mediate blasticidin S resistance in malaria parasites. (19th July 2013)

• Record Type: Journal Article
• Authors: Mira‐Martínez, Sofía; Rovira‐Graells, Núria; Crowley, Valerie M.; Altenhofen, Lindsey M.; Llinás, Manuel; Cortés, Alfred
• Is Part Of: Cellular microbiology. Volume 15:Number 11(2013:Nov.)
• Page Start: 1913
• Page End: 1923
• Publication Date: 2013-07-19
• Subjects: Microbiology -- Periodicals; Cytology -- Periodicals; Host-parasite relationships -- Periodicals; Microbiology -- Periodicals; Cells -- Periodicals; Microbiologie -- Périodiques; Microbiologie; Relation hôte-parasite; Cytologie; Cellule; Réponse cellulaire; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); 579.05
• DOI: 10.1111/cmi.12162
• Languages: English
• ISSNs: 1462-5814

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Malaria parasites induce changes in the permeability of the infected erythrocyte membrane to numerous solutes, including toxic compounds. In <italic>Plasmodium falciparum</italic>, this is mainly mediated by PSAC, a broad‐selectivity channel that requires the product of parasite <italic>clag3</italic> genes for its activity. The two paralogous <italic>clag3</italic> genes, <italic>clag3.1</italic> and <italic>clag3.2</italic>, can be silenced by epigenetic mechanisms and show mutually exclusive expression. Here we show that resistance to the antibiotic blasticidin S (BSD) is associated with switches in the expression of these genes that result in altered solute uptake. Low concentrations of the drug selected parasites that switched from <italic>clag3.2</italic> to <italic>clag3.1</italic> expression, implying that expression of one or the other <italic>clag3</italic> gene confers different transport efficiency to PSAC for some solutes. Selection with higher BSD concentrations resulted in simultaneous silencing of both <italic>clag3</italic> genes, which severely compromises PSAC formation as demonstrated by blocked uptake of other PSAC substrates. Changes in the expression of <italic>clag3</italic> genes were not accompanied by large genetic rearrangements or mutations at the <italic>clag3</italic> loci or elsewhere in the genome. These resultsdemonstrate that malaria parasites can become resistant to toxic compounds such as drugs by epigenetic switches in the expression of genes necessary for the formation of solute channels.</p> </abstract>