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.

Macrophage Polarization in Leishmaniasis: Broadening Horizons

“…In contrast, the activation of Th2 lymphocytes, which produce IL-4 and IL-13 cytokines, induces the M2 profile caractherized by polyamine biosynthesis via activation of the enzyme arginase (arg) and production of urea and L -ornithine, which are beneficial for Leishmania intramacrophage growth favoring parasite survival in the infected macrophages and disease progression ( 22 , 24 ).…”

Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis

“…The differentiation of CD4+ T cells in T helper type (Th)1 upon antigen recognition on Major Histocompatibility Complex (MHC) II is predominantly associated with the development of a proinflammatory response, characterized by secretion of TNF-α, IL-1β, IL-6, IL-12, IL-18, and IL-23 cytokines; increased production of highly microbicidal ROS and reactive nitrogen species (RNS) (e.g., hydrogen peroxide, superoxide, hydroxyl radicals, and NO) via activation of the NADPH oxidase complex and inducible nitric oxide synthase (iNOS), respectively; and enhanced phagocytosis, leading to infection control especially in experimental models [54,55]. Meantime, an anti-inflammatory phenotype is correlated with a predominant Th2 response characterized by the production of IL-4, IL-13, IL-10, and Transforming Growth Factor (TGF)-β cytokines; enhanced arginase activity; polyamine biosynthesis; and IL-21-mediated down-regulation of iNOS, TNF-α, and Toll-like receptor (TLR)-4, favoring intracellular proliferation of Leishmania parasites and disease progression [56,57] (Figure 2). Additionally, the role of other T cell subtypes in Leishmania pathogenesis, such as T regulatory cells (Treg), CD8+ T cytotoxic, and Th17 effector cells, is coming to light [20,58,59].…”

Parasite Sensing of Host Nutrients and Environmental Cues

“…Infected patients exhibit hypocholesterolemia, and high serum cholesterol is associated with resistance to infection. The modulation of host cholesterol metabolism by L. donovani entails a sophisticated strategy involving modulation Abebe et al, 2012Abebe et al, , 2013Alkaitis et al, 2016;Dowling et al, 2010;Fox et al, 2004;Franç a-Costa et al, 2015;Meireles et al, 2017;Muxel et al, 2018;Ren et al, Alkaitis et al, 2016;Lamour et al, 2015;Planche et al, 2005;Ren et al, 2018 Asparagine Important for Pb sexual development and Pb liver stage Altered upon Pf infection Nagaraj et al, 2015;Olszewski et al, 2009;Ren et al, 2018 Lipids Cholesterol Essential to most parasites; usage by Ld and uptake by Tc and Pf; Ld modulation of host metabolism (through miR-122)…”