Leishmania Eukaryotic Initiation Factor (LeIF) Inhibits Parasite Growth in Murine Macrophages

Abstract

The leishmaniases constitute neglected global public health problems that require adequate control measures, prophylactic clinical vaccines and effective and non-toxic drug treatments. In this study, we explored the potential of Leishmania infantum eukaryotic initiation factor (LieIF), an exosomal protein, as a novel anti-infective therapeutic molecule. More specifically, we assessed the efficacy of recombinant LieIF, in combination with recombinant IFN-γ, in eliminating intracellular L. donovani parasites in an in vitro macrophage model. J774A.1 macrophages were initially treated with LieIF/IFN-γ prior to in vitro infection with L. donovani stationary phase promastigotes (pre-infection treatment), and resistance to infection was observed 72 h after infection. J774A.1 macrophages were also treated with LieIF/IFN-γ after L. donovani infection (post-infection treatment), and resistance to infection was also observed at both time points tested (19 h and 72 h) after infection. To elucidate the LieIF/IFN-γ-induced mechanism(s) that mediate the reduction of intracellular parasite growth, we examined the generation of potent microbicidal molecules, such as nitric oxide (NO) and reactive oxygen species (ROS), within infected macrophages. Furthermore, macrophages pre-treated with LieIF/IFN-γ showed a clear up-regulation in macrophage inflammatory protein 1α (MIP-1α) as well as tumor necrosis factor alpha (TNF-α) expression. However, significant different protein levels were not detected. In addition, macrophages pre-treated with LieIF/IFN-γ combined with anti-TNF-α monoclonal antibody produced significantly lower amounts of ROS. These data suggest that during the pre-treatment state, LieIF induces intramacrophage parasite growth inhibition through the production of TNF-α, which induces microbicidal activity by stimulating NO and ROS production. The mechanisms of NO and ROS production when macrophages are treated with LieIF after infection are probably different. Overall, these results indicate that LieIF is a good candidate for use as an anti-leishmanial molecule.

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

“…The excessive Th1 response and the increased levels of IFN-γ observed in P2X7 KO mice in this study may be related to the failure in control L. amazonensis infection because macrophages pretreated with IFN-γ are more susceptible to Leishmania infection [34]. In addition, P2X7 receptor activation by ATP potentiated IFNγ-induced NO production in microglia [35].…”

Asteraceae Artemisia campestris and Artemisia herba-alba Essential Oils Trigger Apoptosis and Cell Cycle Arrest in Leishmania infantum Promastigotes

“…It was reported previously by Zahir et al, 2015 [50], that induced decrease of reactive oxygen species level by Euphorbia plant extract is implicated in the death mechanism of Leishmania parasites and could be responsible for the caspase-independent shift from apoptosis to massive necrosis. Furthermore, studies done previously by our team [51] have shown that increase in reactive oxygen species induced by Leishmania Eukaryotic Initiation Factor (LeIF) in murine macrophages is implicated in the enhancing resistance of macrophages J774 to Leishmania infection.…”

Reduction of Inflammatory Response by Way of Oxidative Stress with San Huang Decoction (SHD) In Perioperative Care: A Randomized Clinical Trial

“…We believe that suitable control of extensive inflammation should benefit for wound healing because excessive and prolonged inflammation results in delayed healing and increased scar formation [45]. The volume of drainage fluid from breast operative wound delegate the delay of wound and the transition from inflammation to proliferation in wound tissue [46]. Our results showed that the duration and amounts of postoperative drainage fluid reduced significantly with SHD treatment.…”