Metabolic Pathways Required for the Intracellular Survival of Leishmania

Abstract

Leishmania spp. are sandfly-transmitted parasitic protozoa that cause a spectrum of important diseases and lifelong chronic infections in humans. In the mammalian host, these parasites proliferate within acidified vacuoles in several phagocytic host cells, including macrophages, dendritic cells, and neutrophils. In this review, we discuss recent progress that has been made in defining the nutrient composition of the Leishmania parasitophorous vacuole, as well as metabolic pathways required by these parasites for virulence. Analysis of the virulence phenotype of Leishmania mutants has been particularly useful in defining carbon sources and nutrient salvage pathways that are essential for parasite persistence and/or induction of pathology. We also review data suggesting that intracellular parasite stages modulate metabolic processes in their host cells in order to generate a more permissive niche.

Gluconeogenesis in Leishmania mexicana

“…It could explain, in part, the minimal participation of PPDK and PEPCK in gluconeogenesis observed in promastigotes and amastigotes, respectively. Both life cycle stages are quite different at morphologic and metabolic levels (3,(42)(43)(44). Interestingly, our results also revealed differences in the degree of flexibility to perturbations of the central metabolic network between promastigotes and amastigotes.…”

Regulation Dynamics of Leishmania Differentiation: Deconvoluting Signals and Identifying Phosphorylation Trends

“…In mammalian cells, cAMP-dependent PKA has four regulatory subunit isoforms that negatively regulate activity of its catalytic kinase subunit (31). In African trypanosomes, extracellular parasites that cause African sleeping sickness, PKA activity is independent of cAMP, 3 and their genomes contain only a single regulatory subunit gene (TbPKAR1, Tb11.02.2210). In contrast, the genomes of the intracellular trypanosomatids T. cruzi and Leishmania contain genes that encode for two different regulatory subunit homologs, Linj.13.0160 and Linj.34.2680, of which the former is likely the ortholog of TbPKAR1.…”

“…As extracellular promastigotes, parasites are surrounded by the sugar-rich, slightly alkaline environment of the fly's mid-gut, which has a mean temperature of 26°C. Intracellular amastigotes encounter the sugar-poor, fatty-acid-and amino-acid-rich acidic environment of the phagolysosome at the elevated temperatures of the skin and viscera (3,4). To enable molecular insight into Leishmania development, an axenic host-free system that simulates Leishmania differentiation by exposing promastigotes to a lysosome-like environment was developed (5-7).…”

Cytosolic NADPH Homeostasis in Glucose-starved Procyclic Trypanosoma brucei Relies on Malic Enzyme and the Pentose Phosphate Pathway Fed by Gluconeogenic Flux

“…This cell cycle arrest phenotype may be caused by depletion of ribulose 5-phosphate for nucleotide synthesis. Supplementation with exogenous amino acids stimulates the growth of intracellular amastigotes (64), suggesting adaptation of the amastigotes to the sugar-poor but amino acid-rich environment. In the gut and hemolymph of the insect vector of T. brucei, a gluconeogenic flux may not only contribute to maintain the redox balance of the cell, but be crucial for synthesizing ribulose 5-phosphate and certain sugars for cell surface glycoconjugates, as shown in Leishmania (62).…”