Human genetic polymorphism and Leishmaniasis.

Leishmaniasis is a disease of the subtropical and tropical spheres of the earth and has various clinical manifestations. The different form of leishmaniasis includes cutaneous leishmaniasis, mucocutaneous leishmaniasis, most lethal visceral leishmaniasis and PKDL form. These different forms depend on many factors such as parasite and vector species, geographical, environmental conditions and population ethnicity. Host genetic factors have been widely investigated for their role in developing the disease in various infections. There are several reports on associations or resistance between candidate gene polymorphisms and the risk and outcome of Leishmania infection. Polymorphism in genes involved in both innate and adaptive immune systems, as well as genes of metabolic processes contributes to disease manifestation. The wide availability and advancement of molecular techniques permits to exploration of hereditary factors related to leishmaniasis. Many candidate gene studies were conducted on family-based and population to identify novel biomarkers for understanding disease pathogenesis pathways and possible drug targets. This comprehensive review presents an update on various human genes polymorphism that influence the outcome of different forms of Leishmania infection in endemic regions of the world. Various electronic databases were searched systematically for relevant publications and thoroughly analyzed. Most of the candidate gene studies were found with discrepancies in findings. Genetic and functional studies with adequate power are needed to validate the contribution of host genes in susceptibility or resistance towards Leishmania infection and understanding pathogenesis.

Zinc depletion promotes apoptosis-like death in drug-sensitive and antimony-resistance Leishmania donovani.

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.