Abstract
Visceral leishmaniasis (VL) is one of the most neglected tropical diseases for which no vaccine exists. In spite of extensive efforts, no successful vaccine is available against this dreadful infectious disease. To support vaccine development, an immunoinformatics approach was applied to screen potential MHC class-II-restricted epitopes that can activate the immune cells. Initially, 37 epitopes derived from six stage-dependent, overexpressed antigens were predicted, which were presented by at least 26 diverse MHC class-II allele. Based on a population coverage analysis and human leukocyte antigen cross-presentation ability, six of the 37 epitopes were selected for further analysis. Stimulation with synthetic peptide alone or as a cocktail triggered intracellular IFN-γ production. Moreover, specific IgG antibodies were detected in the serum of active VL cases against P1, P4, P5, and P6 in order to evaluate the peptide effect on the humoral immune response. Additionally, most of the peptides, except P2, were found to be non-inducers of CD4+ IL-10 against both active VL as well as treated VL subjects. This finding suggests there is no role of these peptides in the pathogenesis of Leishmania. Peptide immunogenicity was validated in BALB/c mice immunized with a cocktail of synthetic peptide emulsified in complete Freund’s adjuvant/incomplete Freund’s adjuvant. The immunized splenocytes induced strong spleen cell proliferation upon parasite re-stimulation. Furthermore, increased IFN-γ, interleukin-12, IL-17, and IL-22 production augmented with elevated nitric oxide (NO) synthesis is thought to play a crucial role in macrophage activation. In this investigation, we identified six MHC class-II-restricted epitope hotspots of Leishmania antigens that induce CD4+ Th1 and Th17 responses, which could be used to potentiate a human universal T-epitope vaccine against VL.
Highlights
The different forms of leishmaniasis comprise an imperative group of neglected tropical diseases [1, 2], which influence and impact “the bottom billion” of population living in poverty by inducing disfiguration, loss of productivity, and a burden of 3.3 million disability-adjusted life years [3,4,5]
The selected antigens were screened for plausible 15mer MHC class-II epitopes (HLA– DRB1*0101) using three different types of software
Various techniques have been applied to address the need for antileishmania vaccine candidates that are effective against leishmaniasis
Summary
The different forms of leishmaniasis comprise an imperative group of neglected tropical diseases [1, 2], which influence and impact “the bottom billion” of population living in poverty by inducing disfiguration, loss of productivity, and a burden of 3.3 million disability-adjusted life years [3,4,5]. Immune activation by CD8+ T-cells through granzyme activities and by the release of IFN-γ is reported, CD4+ T-cells are pre-dominantly involved in immune cell activation against Leishmania by producing IFN-γ, macrophage migration inhibitory factor, and tumor necrosis factor/lymphotoxin (TNF/LT) [13]. Diverse cytokines such as interleukin-4, IL-10, and transforming growth factor β, have been shown to modulate Th1 responses, deter macrophage activation, and exacerbate the disease [14, 15]
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