Abstract
BackgroundLeishmaniases are a group of neglected tropical parasitic diseases, mainly affecting vulnerable populations of countries with poor socioeconomic status. Development of efficient vaccines is a priority due to the increasing incidence of drug resistance and toxicity to current treatments. In the search for a safe and efficient protective vaccine for human and dog visceral leishmaniases, we analyzed the suitability of the immunomodulatory drug sirolimus (SIR) to boost a preventive DNA vaccine against leishmaniasis. SIR is an already marketed drug that has been described to boost immune protection against different disease models and has also emerged as a promising therapeutic drug against L. major.MethodsSyrian hamsters were treated with SIR concomitantly with the administration of a DNA vaccine formulation consisting in four plasmids carrying the Leishmania genes LACK, TRYP, PAPLE22 and KMPII, respectively. Two weeks after the last vaccination, the animals were infected intraperitoneally with L. infantum parasites. Five weeks post-infection the parasite load was measured by real-time PCR in target tissues and immune response was evaluated by determining anti-Leishmania specific antibodies in combination with cytokine expression in the spleen.ResultsOur results show that the DNA vaccine itself efficiently reduced the burden of parasites in the skin (P = 0.0004) and lymph nodes (P = 0.0452). SIR administration also enhanced the protection by reducing the parasite load in the spleen (P = 0.0004). Vaccinated animals with or without SIR co-treatment showed lower IFN-γ expression levels than those found in the spleen of control animals. mRNA expression levels of NOS2 and IL-10 were found to be significantly higher in the vaccinated plus SIR treated group.ConclusionsCo-administration of SIR enhances a DNA vaccination regimen against L. infantum, improving the reduction of parasite load in skin, lymph node and spleen. The analysis of immune markers in the spleen after challenge suggests that the trend to recover naïve levels of IFN-γ and IL-10, and the concurrent higher expression of NOS2, may be responsible for the protection induced by our vaccine co-administered with SIR.
Highlights
Leishmaniases are a group of neglected tropical parasitic diseases, mainly affecting vulnerable populations of countries with poor socioeconomic status
We have previously studied the effect of a DNA vaccine carrying the Leishmania genes LACK, tryparedoxin peroxidase (TRYP), PAPLE22 and kineto‐ plastid membrane protein-11 (KMPII) in a hamster model of leishmaniasis
Leishmania-specific immunoglobulin G (IgG) production was reduced in group V animals when compared to group C (ψ = 0.12, 95% Confidence Interval (CI): 0.02–0.22, P = 0.0475), and S + V (ψ = − 0.12, 95% CI: − 0.22–0.04, P = 0.0180)
Summary
Leishmaniases are a group of neglected tropical parasitic diseases, mainly affecting vulnerable populations of countries with poor socioeconomic status. In the search for a safe and efficient protective vaccine for human and dog visceral leishmaniases, we analyzed the suitability of the immunomodulatory drug sirolimus (SIR) to boost a preventive DNA vaccine against leishmaniasis. Leishmaniasis is a neglected disease caused by protozoan parasites belonging to the genus Leishmania. Transmitted by infected female sand fly vectors, Leishmania spp. are responsible for over 1,500,000 human cases, resulting in more than 20,000 deaths per year, with the highest impact on the poorest people in developing countries [1]. CD4+ Th1 cells activate CD8+ T cells which are required for optimal resistance, providing beneficial cytokines such as IFN-γ and killing parasite-infected cells [6, 7]. Unlike experimental VL in mice, most infected people develop asymptomatic infections, which correlates with the activation of specific cell-mediated immunity and a Th1-proinflammatory immune response [8]. The active disease, has been linked to high antibody levels and a progressive Th2-deactivating immune response in the presence of a strong inflammatory reaction [9]
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