Arginase and its mechanisms in Leishmania persistence

Abstract

Leishmaniasis is a neglected infectious disease with clinical presentations ranging from asymptomatic or mild symptoms to chronic infection and eventual death. The mechanisms of disease susceptibility and pathology have been extensively studied, but there are no steadfast rules regarding leishmaniasis. A Th1 response is usually associated with infection control, while a predominant Th2 response is detrimental to the patient. In this scenario, the enzymes arginase and inducible nitric oxide synthase represent two possible pathways of immune response. While the former contributes to parasite replication, the latter is crucial for its control. In the present review, we collected study results that associate arginase expression in patients and in experimental models with disease susceptibility/chronicity and show some proposed mechanisms that explain the role of arginase in maintaining Leishmania infection, including polyamine and thiol synthesis, tissue‐resident macrophage (TRM) proliferation and activation and T‐cell suppression and exhaustion.

A Cytokine Network Balance Influences the Fate of Leishmania (Viannia) braziliensis Infection in a Cutaneous Leishmaniasis Hamster Model

“…Arginase, an enzyme found in all Leishmania strains and produced by macrophages, stimulates parasite replication and inhibits nitric oxide function ( 36 ). The basal arg expression was high in hamster skin.…”

Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise

“…An increased arginase activity with the associated reduction in nitric oxide appears to be a key contributor for the above listed disease states and numerous studies have investigated the beneficial effect of arginase inhibitors in vitro and in clinical studies (summarized in [23][24][25]). In Leishmania parasites, arginase has similarly been a recent focus of research (reviewed in [26][27][28][29][30][31][32]).…”

“…Critical downstream reactions are the hypusination and activation of eukaryotic initiation factor 5A (eIF5A) and the formation of trypanothione, which is essential for defense against oxidative stress. Recent studies have highlighted the importance of polyamines and trypanothione for parasite proliferation and infectivity and validate the pathway as a potential therapeutic target [26,[29][30][31][32][33][34][35][36][37][38][39][40]. In particular, arginase as the first enzyme of this pathway has been of considerable interest [26,29,31,32,35,36,39].…”

“…Recent studies have highlighted the importance of polyamines and trypanothione for parasite proliferation and infectivity and validate the pathway as a potential therapeutic target [26,[29][30][31][32][33][34][35][36][37][38][39][40]. In particular, arginase as the first enzyme of this pathway has been of considerable interest [26,29,31,32,35,36,39].…”

“…Polarization of macrophages to the M1 phenotype is associated with nitric oxide production and parasite clearance. This type of response is induced by T-helper type 1 (Th1) cells that produce pro-inflammatory cytokines such as IFNγ, TNFα, and IL12 (Figure 3) [27,31,32,50,51]. However, Leishmania parasites have the ability to stimulate differentiation of T cells towards the Th2 subset, which produces the anti-inflammatory cytokines IL4, IL13, and TGFβ.…”