Retracted: Evaluating the immunomodulatory responses of LdODC‐derived MHC Class‐II restricted peptides against VL

Abstract

In a bid to develop a novel immunoprophylactic measure against visceral leishmaniasis (VL), MHC class‐II–restricted epitopes of LdODC were identified by reverse vaccinology approach. Five consensus HLA‐DRB1*0101‐restricted epitopes were screened. The analysis revealed that the set of epitopes was presented by at least 54 diverse MHC class‐II alleles. Based on in silico screening, followed by molecular dynamics simulation, population coverage analysis, and HLA cross‐presentation ability, five best epitopes were evaluated. PBMCs isolated from treated VL subjects, when stimulated with synthetic peptide alone or as a cocktail of peptides, triggered a secretory IFN‐γ, but not the IL‐10 level. Support in this notion came from intracellular cytokine level with a considerable up‐regulated IFN‐γ produced by CD4+ T cells. Also, the enhanced IFN‐γ seemed to be augmented with the activation of macrophages with prominent IL‐12 production. Therefore, it can be concluded that the screened MHC class‐II–restricted epitope hotspots derived from Leishmania ODC can trigger CD4+ T cells, which can skew macrophage functions towards protection. However, a detailed analysis can explore its potentiality as a vaccine candidate.

Validating Immunomodulatory Responses of r-LdODC Protein and Its Derived HLA-DRB1 Restricted Epitopes against Visceral Leishmaniasis in BALB/c Mice

“…Additionally, the in vitro screening of peptides showed significant production of proinflammatory cytokines (CD4+IFN-γ and CD14+IL-12) in the treated cases of VL subjects. However, the production of anti-inflammatory cytokine CD4+IL-10 was not significantly higher ( p ≥ 0.05) [ 16 ].…”

“…Further population coverage and antigen cross-presentation were analyzed and screened by the IEDB population coverage analysis tool and NetMHCpan 2.3, respectively. Additionally, a 100 ns molecular dynamics simulation study was performed for each selected epitope at 300 K. The shortlisted epitopes were synthesized by Peptide2.0 (Chantilly, VA, USA) with 95% purity [ 16 ]. The purified protein and synthesized peptides were stored at −80 °C for further in vivo study.…”

“…During exposure to Leishmania infection, macrophages engulf the internalized parasites and digest them [ 13 ], and the digested fragments of parasites are presented on the surface of macrophages or other antigen-presenting cells through collaborating with MHC molecules [ 14 ]. Fragmented peptides on the surface of antigen-presenting cells interact with T cells or newly activated macrophages for the generation of proinflammatory cytokines such as IFN-γ and IL-12 [ 12 , 15 , 16 ]. Apart from cytokine production, the antigen-stimulated macrophages increase the expression of MHC Class-II molecules [ 17 ].…”

“…Apart from cytokine production, the antigen-stimulated macrophages increase the expression of MHC Class-II molecules [ 17 ]. It has been found that the addition of adjuvants with antigen has significantly improved the immunoprophylactic efficacy, and hence vaccine potential [ 16 , 18 ]. In an earlier study, polypeptide-based vaccines, Leish-IIIf with adjuvants GLA-SE and MPL-A demonstrated effective immune responses against the Leishmania parasite [ 19 , 20 ].…”

“…As mentioned in the literature, the polyamine biosynthesis pathway and its derived byproducts played a crucial role in the survival and proliferation of the Leishmania parasite [ 23 , 24 , 25 ]. An in vitro and in vivo experiment study reported that ODC protein, a rate-limiting enzyme of polyamine biosynthesis pathway [ 26 ], ODC DNA construct [ 27 ], as well as its derived synthetic peptides [ 16 , 28 ] have the potential to generate a significant amount of pro-inflammatory cytokines and promote protection against Leishmania infection. Another study reported HIV-1 reverse transcriptase (RT) with fused ornithine decarboxylase (ODC) as a potential vaccine candidate as it strengthened a strong Th1 immune response against HIV in mice models [ 29 ].…”