Abstract
Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alternates between sand fly and human host. To survive and establish infections, Leishmania parasites scavenge and internalize nutrients from the host. Nevertheless, host cells presents mechanism like nutrient restriction to inhibit microbial growth and control infection. Zinc is crucial for cellular growth and disruption in its homeostasis hinders growth and survival in many cells. However, little is known about the role of zinc in Leishmania growth and survival. In this study, the effect of zinc on the growth and survival of L.donovani was analyzed by both Zinc-depletion and Zinc-supplementation using Zinc-specific chelator N, N, N', N'–tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) and Zinc Sulfate (ZnSO4). Treatment of parasites with TPEN rather than ZnSO4 had significantly affected the growth in a dose- and time-dependent manner. The pre-treatment of promastigotes with TPEN resulted into reduced host-parasite interaction as indicated by decreased association index. Zn depletion resulted into flux in intracellular labile Zn pool and increased in ROS generation correlated with decreased intracellular total thiol and retention of plasma membrane integrity without phosphatidylserine exposure in TPEN treated promastigotes. We also observed that TPEN-induced Zn depletion resulted into collapse of mitochondrial membrane potential which is associated with increase in cytosolic calcium and cytochrome-c. DNA fragmentation analysis showed increased DNA fragments in Zn-depleted cells. In summary, intracellular Zn depletion in the L. donovani promastigotes led to ROS-mediated caspase-independent mitochondrial dysfunction resulting into apoptosis-like cell death. Therefore, cellular zinc homeostasis in Leishmania can be explored for new drug targets and chemotherapeutics to control Leishmanial growth and disease progression.
Highlights
Leishmaniasis, a neglected tropical disease affecting 350 million people, is prevalent across 98 countries worldwide with higher incidence in tropic and sub-tropical region
Our present study demonstrated that the growth and survival of the Leishmania parasite is inhibited by the depletion of intracellular Zn
Whereas Zn supplementation alone or along with chelator had no inhibitory effect on survival and proliferation, indicating that the growth and proliferation of the Leishmania promastigotes depends on the availability of Zn
Summary
Leishmaniasis, a neglected tropical disease affecting 350 million people, is prevalent across 98 countries worldwide with higher incidence in tropic and sub-tropical region. The most severe one, VL has a disease burden of 0.2 to 0.4 million cases with a mortality rate of 20,000 to 40,000 reported per year [1]. L. donovani, the causative agent of Indian VL, is an obligate intracellular digenetic protozoan parasite that alternate between an insect and a mammalian host during its life cycle. It harbours inside the sandfly midgut and the macrophages of the mammalian host [3, 4]. The host presents several mechanisms to control the infection, one of which is nutrient restriction, known as nutritional immunity [5]
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