Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
Sci Rep. 2017 Sep 5;7(1):10488. doi: 10.1038/s41598-017-10041-6.
Micronutrients are essential for survival and growth for all the organisms including pathogens. In this manuscript, we report that zinc (Zn) chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethylenediamine (TPEN) affects growth and viability of intracellular pathogen Leishmania donovani (LD) by a concentration and time dependent manner. Simultaneous addition of zinc salt reverses the effect of TPEN. Further experiments provide evidence of apoptosis-like death of the parasite due to Zn-depletion. TPEN treatment enhances caspase-like activity suggesting increase in apoptosis-like events in LD. Specific inhibitors of cathepsin B and Endoclease G block TPEN-induced leishmanial death. Evidences show involvement of reactive oxygen species (ROS) potentially of extra-mitochondrial origin in TPEN-induced LD death. Pentavalent antimonials remained the prime source of treatment against leishmaniasis for several decades; however, antimony-resistant Leishmania is now common source of the disease. We also reveal that Zn-depletion can promote apoptosis-like death in antimony-resistant parasites. In summary, we present a new finding about the role of zinc in the survival of drug sensitive and antimony-resistant LD.
微量营养素是所有生物体（包括病原体）生存和生长所必需的。在本手稿中，我们报告锌（Zn）螯合剂 N，N，N'，N'-四（2-吡啶基甲基）-1,2-乙二胺（TPEN）以浓度和时间依赖的方式影响细胞内病原体利什曼原虫（LD）的生长和活力。同时添加锌盐可逆转 TPEN 的作用。进一步的实验提供了证据表明，由于缺锌，寄生虫会发生类似于凋亡的死亡。TPEN 处理可增强半胱天冬酶样活性，表明 LD 中凋亡样事件增加。组织蛋白酶 B 和内切核酸酶 G 的特异性抑制剂可阻止 TPEN 诱导的利什曼原虫死亡。有证据表明，活性氧物质（ROS）可能来自线粒体以外的来源，参与了 TPEN 诱导的 LD 死亡。五价锑仍然是治疗数十年间利什曼病的主要药物；然而，现在对锑有抗药性的利什曼原虫已成为该病的常见来源。我们还发现，锌耗竭可促进对锑有抗药性的寄生虫发生类似于凋亡的死亡。总之，我们提出了一个关于锌在敏感药物和抗锑 LD 生存中的作用的新发现。
