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.
Highlights
Protozoa belonging to the order Kinetoplastida and the genus Leishmania constitute an important group of more than 20 species and subspecies of parasites that are transmitted to human or animals by sandfly vectors [1]
Since previous reports showed that Leishmania Eukaryotic Initiation Factor (LeIF) in IFN-c activated macrophages and monocytes induces secretion of IL-12 [18,19,26] a cytokine necessary for the development of specific immunity towards a Th1 phenotype [24,25], we investigated the effect of Leishmania infantum eukaryotic initiation factor (LieIF) on the susceptibility of MWs to L. donovani infection
In IFN-c- primed bone marrow-derived macrophages, L. donovani promastigotes induce the secretion of nitric oxide (NO), which plays an essential role in the control of Leishmania infection by these macrophages [49,50]
Summary
Protozoa belonging to the order Kinetoplastida and the genus Leishmania constitute an important group of more than 20 species and subspecies of parasites that are transmitted to human or animals by sandfly vectors [1]. These protozoa cause Leishmaniasis, a group of diseases characterised by a wide spectrum of clinical manifestations, ranging from self-healing skin ulcers (e.g. Leishmania major) to disfiguring mucosal lesions (e.g. Leishmania braziliensis), or fatal visceral infections (e.g. Leishmania donovani) [2]. Leishmania spp. have a digenetic life cycle, existing in two distinct forms, the flagellated promastigotes in the gut of their sand-fly vectors and the aflagellated amastigotes in the mammalian host. Aflagellated amastigotes replicate by binary fission, rupturing infected macrophages and spreading to uninfected cells, thereby initiating the onset of disease symptoms in the host [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
