Arginine and Polyamines Fate in Leishmania Infection

Abstract

Leishmania is a protozoan parasite that alternates its life cycle between the sand fly and the mammalian host macrophages, involving several environmental changes. The parasite responds to these changes by promoting a rapid metabolic adaptation through cellular signaling modifications that lead to transcriptional and post-transcriptional gene expression regulation and morphological modifications. Molecular approaches such as gene expression regulation, next-generation sequencing (NGS), microRNA (miRNA) expression profiling, in cell Western blot analyses and enzymatic activity profiling, have been used to characterize the infection of murine BALB/c and C57BL/6 macrophages, as well as the human monocytic cell-lineage THP-1, with Leishmania amazonensis wild type (La-WT) or arginase knockout (La-arg ^- ). These models are being used to elucidate physiological roles of arginine and polyamines pathways and the importance of arginase for the establishment of the infection. In this review, we will describe the main aspects of Leishmania-host interaction, focusing on the arginine and polyamines pathways and pointing to possible targets to be used for prognosis and/or in the control of the infection. The parasite enzymes, arginase and nitric oxide synthase-like, have essential roles in the parasite survival and in the maintenance of infection. On the other hand, in mammalian macrophages, defense mechanisms are activated inducing alterations in the mRNA, miRNA and enzymatic profiles that lead to the control of infection. Furthermore, the genetic background of both parasite and host are also important to define the fate of infection.

Keywords: L-arginine; amastigote; arginase; nitric oxide; nitric oxide synthase; ornithine; polyamine pathway; promastigote.

FIGURE 1

Leishmania L-arginine metabolism. L-arginine metabolic pathways in Leishmania to produce polyamines as well as the interconnection with glutamate and proline metabolism. L-arginine supplies citrulline and nitric oxide (NO) production. Ornithine supplies proline, glutamate and putrescine production, as well as the interconvertion of glutamate, proline and ornithine. Putrescine is the first polyamine that can form spermidine and spermine, essential for parasite growth. Spermidine is the substrate for spermine and trypanothione production. ADC, arginine decarboxylase; AOCT, N-acetylornithine carbamoyltransferase; AOD, acetylornithine deacetylase; AdoMetDC, adenosylmethionine decarboxylase; ASS, argininosuccinate synthase; G5K, glutamate 5-kinase; G5SDH, glutamate-5-semialdehyde dehydrogenase; GspS, glutathionylspermidine synthase; NOS-like, nitric oxide synthase-like; OAT, ornithine aminotransferase; OCD, ornithine cyclodeaminase; ODC, ornithine decarboxylase; OTA, ornithine transacetylase; OTC, ornithine transcarbamylase; P5CDH, pyrroline-5-carboxylate dehydrogenase; P5CR, pyrroline 5-carboxilate reductase; PRODH, proline dehydrogenase; PR, proline racemase; SGDS, succinylglutamate desuccinylase; SpdS, spermidine synthase; SpmS, spermine synthase and TryS, trypanothione synthase.

FIGURE 2

Metabolic fate of L-arginine in Leishmania infected macrophage. L-arginine uptake in the macrophage occurs mostly through CAT2B transporter. Once inside the macrophage, the amino acid is directed to nitric oxide (NO) or polyamines synthesis. NO is produced through NOS2 activity. Arginase (ARG) activity produces ornithine that is further decarboxylated by ornithine decarboxylase (ODC) producing putrescine, a substrate for spermidine synthase (SpdS) and spermine synthase (SpmS) producing spermidine and spermine, respectively. Some intermediate metabolites may cross phagolysossome and the parasite plasmatic membrane. These transporters have not been described yet. The L-arginine uptake occurs by amino acid permease 3 (AAP3) over the parasite plasmatic membrane and to glycosome for polyamines production by the parasite.