Apoptosis in Leishmania species & its relevance to disease pathogenesis

Abstract

Apoptosis is a morphologically distinct form of cell death necessary for embryogenesis, tissue homeostasis and disease control in metazoans. Earlier, it was thought that apoptosis is the prerogative of multicellular organisms. However, it is now evident that unicellular organisms are also capable of undergoing apoptosis. In the context of Leishmania spp., a unicellular eukaryote responsible for causing leishmaniasis, the process of apoptosis is important for successful survival. The flagellated promastigote form of the parasite resides in the midgut of the insect vector, the female sandfly and at this niche; the cell fittest to survive to pass onto the pharynx of the fly is selected by eliminating unfit cells through apoptosis. Within the mammalian host, inside the macrophage, apoptosis is necessary to regulate cell numbers and to minimize immune reactions. With most apoptosis inducing stimuli, L. donovani shows typical features of apoptotic death like cell shrinkage, nuclear condensation and DNA fragmentation. Agents capable of precipitating apoptosis in this parasite include anti-leishmanial drugs like antimony, amphotericin B, pentamidine and miltefosine. Other agents like heat shock, treatment with staurosporine, knocking out centrin gene also precipitate apoptosis of the parasites. A pivotal role in cellular apoptosis is played by the single mitochondrion of Leishmania spp., where a fall or increase in mitochondrial potential leads to cell death by apoptosis. Ca²⁺ appears to be a vital ion involved in Leishmania apoptosis and partial inhibition of cytosolic Ca²⁺ increase achieved by chelating extracellular or intracellular Ca²⁺ during oxidative stress results in significant rescue of the fall of the mitochondrial membrane potential and consequently apoptosis. Elucidation of the molecular events linked to apoptotic death of Leishmania spp. might help define a more comprehensive view of the cell death machinery in terms of evolutionary origin and identify new target molecules for chemotherapeutic drug development and therapeutic intervention.