Effect of phospholipase A2 inhibitors during infection caused by Leishmania (Leishmania) amazonensis

Maria L A C Bordon,Marcos H Toyama,Susan Pereira Ribeiro,Daniela De O Toyama,Márcia D Laurenti,Luiz Felipe D Passero

doi:10.1186/s40409-018-0156-9

Abstract

BackgroundLipid metabolites play an important role in parasite differentiation and virulence. Studies have revealed that Leishmania sp. uses prostaglandins to evade innate barriers, thus enabling the parasites to survive inside immune cells. Despite the role of the enzyme Phospholipase A2 (PLA2) in prostaglandins production, few studies have investigated the role of parasite PLA2 during the interaction between L. (L.) amazonensis and the host (in vitro and in vivo) immune cells.MethodsIn the present work, the leishmanicidal effect of PLA2 inhibitors, methyl arachidonyl fluorophosphonate (MAFP), bromoenol lactone (BEL) and aristolochic acid (AA) were investigated in vitro (promastigote and intracellular amastigote forms of L. (L.) amazonensis) and during in vivo infection using BALB/c mice.ResultsThe aforementioned inhibitors were deleterious to promastigote and amastigote forms of the L. (L.) amazonensis and were non-toxic to peritoneal macrophages from BALB/c mice. L. (L.) amazonensis-infected BALB/c mice treated with the inhibitor BEL presented decreased lesion size and skin parasitism; however, BEL treatment induced hepatotoxicity in BALB/c mice.ConclusionsResults presented herein suggested that PLA2 inhibitors altered L. (L.) amazonensis viability. In spite of liver toxicity, treatment with BEL was the most selective compound in vitro, as well in vivo, resulting in lower skin parasitism in the infected mice. These findings corroborate the role of PLA2 in parasite virulence and maintenance in vertebrate hosts, and suggest that molecules structurally related to BEL should be considered when planning compounds against Leishmania sp.

Highlights

Lipid metabolites play an important role in parasite differentiation and virulence
Leishmanicidal and cytotoxic activities of Phospholipase A2 (PLA2) inhibitors bromoenol lactone (BEL) was the most active PLA2 inhibitor, killing 50% of promastigote forms of L. amazonensis with 15.1 ± 3.7 μM; methyl arachidonyl fluorophosphonate (MAFP) presented intermediate activity (50.5 ± 7.8 μM), followed by aristolochic acid (AA), eliminating promastigote forms with EC50 of 450.1 ± 45.6 μM; miltefosine eliminated promastigote forms with an EC50 of 12.6 ± 2.1 μM (Table 1)
It was observed that BEL was the most selective molecule, followed by MAFP, AA and miltefosine (Table 1)

Summary

Introduction

Lipid metabolites play an important role in parasite differentiation and virulence. Studies have revealed that Leishmania sp. uses prostaglandins to evade innate barriers, enabling the parasites to survive inside immune cells. Following inoculation of Leishmania promastigotes into the dermis of the mammalian host, a parasite metalloproteinase of 63 kDa (gp63) is able to cleave the C3b factor of the complement system into an inactive form (iC3b), which is able to bind to leishmanial lipophosphoglycan (LPG) and even to gp. Following inoculation of Leishmania promastigotes into the dermis of the mammalian host, a parasite metalloproteinase of 63 kDa (gp63) is able to cleave the C3b factor of the complement system into an inactive form (iC3b), which is able to bind to leishmanial lipophosphoglycan (LPG) and even to gp63 These opsonized Leishmania promastigotes bind to CR1 and CR3 macrophage receptors thereby commencing phagocytosis. Interactions between Leishmania and fibronectin receptors will trigger an inflammatory response associated with parasite death [2, 3]

Objectives

Methods

Results

Discussion

Conclusion