The role of eIF2alpha phosphorylation in controlling intracellular development of Leishmania

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The parasitic protozoan Leishmania is the etiological agent of human leishmaniasis worldwide. Leishmania exists in two major developmental stages-free-living promastigotes in the sandfly vector and intracellular amastigotes in the phagolysosome of mammalian macrophages. During its differentiation from promastigote to amastigote forms, Leishmania experiences drastic environmental changes. In order for the parasite to differentiate and replicate within the harsh environment of the phagolysosome, it has to develop several adaptive responses/strategies involving important morphological and biochemical changes and dynamic alterations in the regulation of gene expression. In eukaryotes, one of the most conserved stress response pathways to control translation initiation is the phosphorylation of the alpha-subunit of eukaryotic initiation factor-2 by stress-responsive eIF2alpha kinases, resulting in the reduction of global translation. We have shown recently that eIF2alpha phosphorylation is a prerequisite for amastigote differentiation in macrophages. Slowly replicating amastigotes have to maintain translation rates low in order to adapt to stressful situations in the phagolysosome, such as acidic pH, nutritional and oxidative stresses. Decreased levels of translation in amastigotes coincide with eIF2alpha phosphorylation. Interestingly, we showed that phosphorylation of eIF2alpha is developmentally regulated by a novel cotranslational/ posttranslational mechanism. Such a regulation allows the insect promastigote form to proliferate faster but intracellular amastigotes to divide more slowly, as a strategy to adapt to a highly stressful and dynamic environment and to evade the immune response of the host macrophage. We propose a series of experiments to better understand the molecular mechanism(s) by which intracellular parasites respond to stress and ensure their survival. These studies will provide significant insights in the role that stress and eIF2alpha phosphorylation play in the development of intracellular pathogens.