Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Catalonia, Spain.
Cell Microbiol. 2013 Nov;15(11):1913-23. doi: 10.1111/cmi.12162. Epub 2013 Jul 19.
Malaria parasites induce changes in the permeability of the infected erythrocyte membrane to numerous solutes, including toxic compounds. In Plasmodium falciparum, this is mainly mediated by PSAC, a broad-selectivity channel that requires the product of parasite clag3 genes for its activity. The two paralogous clag3 genes, clag3.1 and clag3.2, 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 clag3.2 to clag3.1 expression, implying that expression of one or the other clag3 gene confers different transport efficiency to PSAC for some solutes. Selection with higher BSD concentrations resulted in simultaneous silencing of both clag3 genes, which severely compromises PSAC formation as demonstrated by blocked uptake of other PSAC substrates. Changes in the expression of clag3 genes were not accompanied by large genetic rearrangements or mutations at the clag3 loci or elsewhere in the genome. These results demonstrate 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.
疟原虫诱导感染红细胞膜对多种溶质（包括有毒化合物）的通透性发生变化。在恶性疟原虫中，这主要是由 PSAC 介导的，PSAC 是一种广谱选择性通道，其活性需要寄生虫 clag3 基因产物的参与。两个平行的 clag3 基因，clag3.1 和 clag3.2，可以通过表观遗传机制沉默，并表现出相互排斥的表达。在这里，我们表明对抗生素硫酸博莱霉素 S（BSD）的抗性与这些基因表达的转换有关，这些转换导致溶质摄取的改变。低浓度的药物选择了从 clag3.2 切换到 clag3.1 表达的寄生虫，这意味着 clag3 基因的表达之一或另一个赋予 PSAC 对某些溶质不同的运输效率。用更高浓度的 BSD 选择导致两个 clag3 基因的同时沉默，这严重损害了 PSAC 的形成，如其他 PSAC 底物摄取受阻所证明的那样。clag3 基因表达的变化没有伴随着 clag3 基因座或基因组其他部位的大的遗传重排或突变。这些结果表明，疟原虫可以通过对形成溶质通道所必需的基因表达的表观遗传开关对有毒化合物（如药物）产生抗性。
