Leishmaniasis comprises of a wide variety of diseases, caused by protozoan parasite belonging to the genus Leishmania. Leishmania parasites undergo different types of stress during their lifetime and have developed strategies to overcome this damage. Identifying the mechanistic approach used by the parasite in dealing with the stress is of immense importance for unfolding the survival strategy adopted by the parasite. Mevalonate kinase (MVK) is an important regulatory factor in the mevalonate pathway in both bacteria and eukaryotes. In this study, we explored the role of Leishmania donovani mevalonate kinase (LdMVK) in parasite survival under stress condition. Hydrogen peroxide (H₂O₂) and menadione, the two known oxidants were used to carry out the experiments. The MVK expression was found to be up regulated ∼2.1 fold and ∼2.3 fold under oxidative stress condition and under the effect of anti-Leishmania drug, AmBisome respectively. The cell viability declined under the effect of MVK inhibitor viz: vanadyl sulfate (VS). The level of intracellular ROS was also found to be increased under the effect of MVK inhibitor. To confirm the findings, LdMVK over expression (LdMVK OE) and LdMVK knockdown (LdMVK KD) parasites were generated. The level of ergosterol, an important component of plasma membrane in L. donovani, was observed and found to be reduced by nearly 60 % in LdMVK KD parasite and increased by nearly 30 % in LdMVK OE parasites as compared to wild type. However, the ergosterol content was found to be elevated under oxidative stress. Furthermore, LdMVK was also found to be associated with maintaining the plasma membrane integrity and also in preventing the peroxidation of cellular lipids when exposed to oxidative stress.

The above data clearly suggests that MVK has a vital role in protecting the parasite from oxidative stress. These findings may also explore the contribution of LdMVK in drug unresponsiveness which may help in future rational drug designing for leishmaniasis.

利什曼病包括由属于利什曼原虫属的原生动物寄生虫引起的多种疾病。利什曼原虫在其一生中会承受不同类型的压力，并且已经制定了克服这种损害的策略。确定寄生虫在处理压力时使用的机械方法对于展开寄生虫采用的生存策略非常重要。甲羟戊酸激酶 (MVK) 是细菌和真核生物甲羟戊酸途径中的重要调节因子。在这项研究中，我们探讨了多诺瓦利什曼原虫甲羟戊酸激酶 ( LdMVK ) 在压力条件下寄生虫存活中的作用。过氧化氢（H ₂ O ₂) 和甲萘醌，这两种已知的氧化剂用于进行实验。发现 MVK 表达在氧化应激条件下和抗利什曼原虫药物 AmBisome 作用下分别上调~2.1 倍和~2.3 倍。在 MVK 抑制剂即硫酸氧钒 (VS) 的作用下，细胞活力下降。在MVK抑制剂的作用下，还发现细胞内ROS的水平增加。为了证实这些发现，产生了LdMVK过表达 ( LdMVK OE ) 和LdMVK敲低 ( LdMVK KD ) 寄生虫。在LdMVK KD 中观察到麦角甾醇（L. donovani质膜的重要组成部分）的水平并发现其降低了近 60%与野生型相比，LdMVK OE寄生虫增加了近 30% 。然而，发现麦角甾醇含量在氧化应激下升高。此外，还发现LdMVK与维持质膜完整性以及防止细胞脂质在暴露于氧化应激时发生过氧化有关。

上述数据清楚地表明，MVK 在保护寄生虫免受氧化应激方面起着至关重要的作用。这些发现还可以探索LdMVK在药物无反应性中的作用，这可能有助于未来针对利什曼病的合理药物设计。