Mining the Proteome of Leishmania donovani for the Development of Novel MHC Class I Restricted Epitope for the Control of Visceral Leishmaniasis

Abstract

Although, the precise host defence mechanism(s) is not completely understood, T cell-mediated immune responses is believed to play a pivotal role in controlling parasite infection. Here we target the stage dependent over expressed gene. Here, the consensus based computational approach was adopted for the screening of potential major histocompatibility complex class I restricted epitopes. Based on the computational analysis and previously published report, a set 19 antigenic proteins derived from Leishmania donovani were screened for further characterization as vaccine candidates. A total of 49 epitopes were predicted, which revealed a comprehensive binding affinity to the 40 different MHC class I supertypes. Based on the population coverage and HLA cross presentation, nine highly promiscuous epitopes such as LTYDDVWTV (P1), FLFPQRTAL(P2), FLFSNGAVV (P3), YIYNFGIRV (P4), YMTAAFAAL (P5), KLLRPFAPL (P6), FMLGWIVTI (P7), SLFERNKRV (P8), and SVWNRIFTL (P9) which have either a high or an intermediate TAP binding affinity were selected for further analysis. Theoretical population coverage analysis of polytope vaccine (P1-P9) revealed more than 92% population. Stimulation with the cocktail of peptide revealed a proliferative CD8 þ T cell response and increased IFN-g production. An upregulated NFkB activity is thought to be play a pivotal role in T cell proliferation against the selected peptide. The Th1-type cytokine profile (presence of IFN-g and absence of IL-10) suggests the potentiality of the cocktail of epitope as a subunit vaccine against leishmaniasis. However, the efficiency of these epitopes to trigger other Th1 cytokines and chemokines in a humanized mice model could explore its plausibility as a vaccine candidate.

An immunoinformatic approach driven by experimental proteomics: in silico design of a subunit candidate vaccine targeting secretory proteins of Leishmania donovani amastigotes

“…This suggests that the in silico designed vaccines with epitopes derived from appropriate protein targets have the potential to progress toward advanced phases of vaccine development for visceral leishmaniasis. While the in silico studies by Khatoon et al [66] and Singh et al [67] largely utilized available genomic databases of L. donovani to select vaccine targets, Dikhit et al [11,70] performed thorough investigations involving in silico, in vitro and in vivo analysis to screen and validate immunogenic epitopes obtained from proteins that are increasingly expressed at the infective parasite stage. Such highly expressed proteins are likely important for physiological and/or infective process of the parasite and thus can be more effective vaccine targets.…”

Vaccine potential of HLA‐A2 epitopes from Leishmania Cysteine Protease Type III (CPC)

“…In agreement with the theory of Trost et al., all the predicted epitopes derived from Leishmania donovani 3‐ectonucleotidase showed either high or moderate binding affinity with HLA‐A*02 molecules and elicited the CD8 + T‐cell response in Leishmania ‐sensitized subjects . Similarly, the cocktail of peptides derived from Leishmania triggered CD8 + IFN‐γ against treated VL subjects as well as in the vaccinated mice model . Therefore, we have predicted the HLA‐A*0201‐restricted CD8 + T‐cell epitope with five most‐commonly used algorithms: SYFPEITHI and BIMAS, RANKPEP, IEDB and Propred1.…”

An immunoinformatic approach driven by experimental proteomics: in silico design of a subunit candidate vaccine targeting secretory proteins of Leishmania donovani amastigotes

“…This suggests that the in silico designed vaccines with epitopes derived from appropriate protein targets have the potential to progress toward advanced phases of vaccine development for visceral leishmaniasis. While the in silico studies by Khatoon et al [104] and Singh et al [105] largely utilized available genomic databases of L. donovani to select vaccine targets, Dikhit et al [11,108] performed thorough investigations involving in silico, in vitro and in vivo analysis to screen and validate immunogenic epitopes obtained from proteins that are increasingly expressed at infective stage of parasite. Such highly expressed proteins are likely important for physiological and/or infective process of the parasite and thus can be more effective vaccine targets.…”