ROS regulate differentiation of visceralizing Leishmania species into the virulent amastigote form.

Parasitology open Pub Date : 2018-01-01 Epub Date: 2018-11-06 DOI:10.1017/pao.2018.15
Yousuf A Khan, Norma W Andrews, Bidyottam Mittra
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引用次数: 13

Abstract

Leishmania virulence and disease development critically depends on the ability of Leishmania promastigotes to infect, differentiate into amastigote forms and replicate inside mammalian host macrophages. Understanding changes associated with amastigote differentiation in axenic culture conditions is key to identifying virulence factors. Here we compared efficiency of the conventional pH-temperature-dependent shift method to induce amastigote differentiation with the recently identified trigger for differentiation mediated by mitochondrial reactive oxygen species (ROS). Using two different visceral leishmaniasis species, L. infantum and. L. donovani, we show that ROS-generating methods such as iron deprivation or exposure to sub-lethal concentrations of H2O2 or menadione are significantly more effective in promoting promastigoteamastigote differentiation than the low pH-high temperature shift, leading to higher survival rates, morphological changes and gene expression patterns characteristic of the amastigote stage. Notably, both H2O2 and menadione-mediated differentiation did not require up-regulation of the mitochondrial electron transport chain (ETC)-associated protein p27, suggesting that treatment with oxidants bypasses the necessity to upregulate mitochondrial activity, a precondition for mROS generation. Our findings confirm that ROS-induced differentiation occurs in multiple Leishmania species, including the medically important visceralizing species, and provide mechanistic rationale for earlier reports demonstrating markedly increased virulence of L. infantum promastigotes pre-treated with oxidative reagents.

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活性氧调节内脏利什曼原虫分化为毒力强的无尾虫。
利什曼原虫的毒力和疾病发展在很大程度上取决于利什曼原虫原鞭毛体感染、分化为无鞭毛体形式和在哺乳动物宿主巨噬细胞内复制的能力。了解与无性系培养条件下无性系分化相关的变化是确定毒力因素的关键。在这里,我们比较了传统的ph -温度依赖转移方法诱导无纺体分化的效率,以及最近发现的由线粒体活性氧(ROS)介导的分化触发器。使用两种不同的内脏利什曼病,婴儿乳杆菌和。L. donovani,我们发现产生ros的方法,如铁剥夺或暴露于亚致死浓度的H2O2或甲氧二酮,比低ph -高温转换更有效地促进promastigoteamastigote分化,导致更高的存活率,形态变化和基因表达模式的特征。值得注意的是,H2O2和甲氧二酮介导的分化都不需要上调线粒体电子传递链(ETC)相关蛋白p27,这表明用氧化剂治疗绕过了上调线粒体活性的必要性,而上调线粒体活性是产生mROS的先决条件。我们的研究结果证实,ros诱导的分化发生在多个利什曼原虫物种中,包括医学上重要的内脏化物种,并为早期报告提供了机制基础,证明经氧化试剂预处理的婴儿利什曼原虫的毒力显着增加。
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