Abstract
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.
Highlights
Zinc as a cofactor of several hundred enzymes is integral for a wide variety of cellular processes that control numerous biological functions[1, 2]
Leishmania donovani (LD) promastigotes were treated with increasing concentrations of zinc chelator TPEN (0–10 μM) for up to 3-days and viability of the parasites were verified by MTT assay
We examined LD growth in a similar condition and about 85% decrease was detected after 72 h by 10 μM TPEN treatment compared to untreated parasites; while 2 μM and 5 μM TPEN reduced LD growth about 40% and 75% respectively
Summary
Zinc as a cofactor of several hundred enzymes is integral for a wide variety of cellular processes that control numerous biological functions[1, 2]. Zinc is an essential trace element in almost all kingdoms of life including humans[2], animals[4], plants[5] and microorganisms[6]. It plays a structural role in zinc fingers, twists and clusters to regulate gene expression[7]. Zinc is well documented to be involved in apoptosis in mammalian cancer cells[3] suggesting this micronutrient has various roles in maintaining crucial cellular mechanisms. The presence of Zn-transporter in Leishmania infantum has been reported underscoring the importance of zinc in crucial cellular functions of this parasite[16]. We report that Zn-depletion by specific chelator N,N,N′,N′-tetrakis (2-pyridinylmethyl)-1,2-ethylenediamine (TPEN) affects LD survival and growth by promoting cell death resembling apoptosis by a reactive oxygen species (ROS) dependent mechanism. Our findings suggest an important role of zinc in survival of both drug-sensitive and antimony-resistant LD
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