El Fadili Karima, Imbeault Michaël, Messier Nadine, Roy Gaétan, Gourbal Benjamin, Bergeron Marc, Tremblay Michel J, Légaré Danielle, Ouellette Marc
Centre de Recherche en Infectiologie du Centre de Recherche du CHUL and Division de Microbiologie, Faculté de Médecine, Université Laval, Québec, Canada.
Antimicrob Agents Chemother. 2008 Feb;52(2):526-33. doi: 10.1128/AAC.01183-07. Epub 2007 Dec 10.
Within the mammalian host, Leishmania donovani is an obligatory intracellular protozoan parasite that resides and multiplies exclusively in the phagolysosomes of macrophages. Leishmania control relies primarily on chemotherapy, with the mainstay being pentavalent antimony (SbV) complexed to carbohydrates in the form of sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime). The mode of action of SbV is still not known precisely. To explore the effect of SbV on macrophage gene expression, a microarray analysis was performed using Affymetrix focus arrays to compare gene expression profiles in noninfected and L. donovani-infected THP-1 monocytic cells treated or not treated with sodium stibogluconate. Under our experimental conditions, SbV changed the expression of a few host genes, and this was independent of whether cells were infected or not infected with Leishmania. Leishmania infection had a greater effect on the modulation of host gene expression. Statistical analyses have indicated that the expression of eight genes was modified by at least twofold upon SbV treatment, with six genes upregulated and two genes downregulated. One gene whose expression was affected by SbV was the heme oxygenase gene HMOX-1, and this change was observed both in the monocytic cell line THP-1 and in primary human monocyte-derived macrophages. Another pathway that was affected was the glutathione biosynthesis pathway, where the expression of the glutamate-cysteine ligase modifier subunit was increased upon SbV treatment. Our analysis has suggested that, under our experimental conditions, the expression of a few genes is altered upon SbV treatment, and some of these encoded proteins may be implicated in the yet-to-be-defined mode of action of SbV.
在哺乳动物宿主体内，杜氏利什曼原虫是一种专性细胞内原生动物寄生虫，仅在巨噬细胞的吞噬溶酶体中生存和繁殖。利什曼病的控制主要依赖化疗，主要药物是与碳水化合物络合的五价锑（SbV），以葡糖酸锑钠（喷他脒）或葡甲胺锑酸盐（葡醛锑）的形式存在。SbV的作用方式仍未完全明确。为了探究SbV对巨噬细胞基因表达的影响，使用Affymetrix聚焦阵列进行了微阵列分析，以比较未感染和感染杜氏利什曼原虫的THP-1单核细胞在经或未经葡糖酸锑钠处理后的基因表达谱。在我们的实验条件下，SbV改变了一些宿主基因的表达，且这与细胞是否感染利什曼原虫无关。利什曼原虫感染对宿主基因表达的调节作用更大。统计分析表明，经SbV处理后，八个基因的表达至少改变了两倍，其中六个基因上调，两个基因下调。一个受SbV影响表达的基因是血红素加氧酶基因HMOX-1，在单核细胞系THP-1和原代人单核细胞衍生的巨噬细胞中均观察到了这种变化。另一个受影响的途径是谷胱甘肽生物合成途径，经SbV处理后，谷氨酸-半胱氨酸连接酶修饰亚基的表达增加。我们的分析表明，在我们的实验条件下，经SbV处理后一些基因的表达发生了改变，其中一些编码的蛋白质可能与SbV尚未明确的作用方式有关。
