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The potential HLA Class I-restricted epitopes derived from LeIF and TSA of Leishmania donovani evoke anti-leishmania CD8+ T lymphocyte response.

ABSTRACT: To explore new protective measure against visceral leishmaniasis, reverse vaccinology approach was employed to identify key immunogenic regions which can mediate long-term immunity. In-depth computational analysis revealed nine promiscuous epitopes which can possibly be presented by 46 human leukocyte antigen, thereby broadening the worldwide population up to 94.16%. This is of reasonable significance that most of the epitopes shared 100% sequence homology with other Leishmania species and could evoke a common pattern of protective immune response. Transporter associated with antigen processing binding affinity, molecular docking approach followed by dynamics simulation and human leukocyte antigen stabilization assay suggested that the best five optimal set of epitopes bind in between ?1 and ?2 binding groove with sufficient affinity and stability which allows the translocation of intact epitope to the cell surface. Fascinatingly, the human leukocyte antigen stabilization assay exhibited a modest correlation with the positive immunogenicity score predicted by class I pMHC immunogenicity predictor. A support for this notion came from ELISA and FACS analysis where the epitopes as a cocktail induced CD8+ IFN-? and Granzyme B levels significantly in treated visceral leishmaniasis subject which suggests the immunogenic ability of the selected epitopes.

SUBMITTER: Dikhit MR

PROVIDER: S-EPMC6154976 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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The potential HLA Class I-restricted epitopes derived from LeIF and TSA of Leishmania donovani evoke anti-leishmania CD8+ T lymphocyte response.

Dikhit Manas Ranjan MR Das Sushmita S Mahantesh Vijaya V Kumar Akhilesh A Singh Ashish Kumar AK Dehury Budheswar B Rout Ajaya Kumar AK Ali Vahab V Sahoo Ganesh Chandra GC Topno Roshan Kamal RK Pandey Krishna K Das V N R VNR Bimal Sanjiva S Das Pradeep P

Scientific reports 20180921 1

To explore new protective measure against visceral leishmaniasis, reverse vaccinology approach was employed to identify key immunogenic regions which can mediate long-term immunity. In-depth computational analysis revealed nine promiscuous epitopes which can possibly be presented by 46 human leukocyte antigen, thereby broadening the worldwide population up to 94.16%. This is of reasonable significance that most of the epitopes shared 100% sequence homology with other Leishmania species and could ...[more]

PMID: 30242172

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Project description:BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.

Project description:The nucleoside hydrolase (NH) of Leishmania donovani (NH36) is a phylogenetic marker of high homology among Leishmania parasites. In mice and dog vaccination, NH36 induces a CD4+ T cell-driven protective response against Leishmania chagasi infection directed against its C-terminal domain (F3). The C-terminal and N-terminal domain vaccines also decreased the footpad lesion caused by Leishmania amazonensis. We studied the basis of the crossed immune response using recombinant generated peptides covering the whole NH36 sequence and saponin for mice prophylaxis against L. amazonensis. The F1 (amino acids 1-103) and F3 peptide (amino acids 199-314) vaccines enhanced the IgG and IgG2a anti-NH36 antibodies to similar levels. The F3 vaccine induced the strongest DTH response, the highest proportions of NH36-specific CD4+ and CD8+ T cells after challenge and the highest expression of IFN-? and TNF-?. The F1 vaccine, on the other hand, induced a weaker but significant DTH response and a mild enhancement of IFN-? and TNF-? levels. The in vivo depletion with anti-CD4 or CD8 monoclonal antibodies disclosed that cross-protection against L. amazonensis infection was mediated by a CD4+ T cell response directed against the C-terminal domain (75% of reduction of the size of footpad lesion) followed by a CD8+ T cell response against the N-terminal domain of NH36 (57% of reduction of footpad lesions). Both vaccines were capable of inducing long-term cross-immunity. The amino acid sequence of NH36 showed 93% identity to the sequence of the NH A34480 of L. amazonensis, which also showed the presence of completely conserved predicted epitopes for CD4+ and CD8+ T cells in F1 domain, and of CD4+ epitopes differing by a single amino acid, in F1 and F3 domains. The identification of the C-terminal and N-terminal domains as the targets of the immune response to NH36 in the model of L. amazonensis infection represents a basis for the rationale development of a bivalent vaccine against leishmaniasis.

Dataset Information

The potential HLA Class I-restricted epitopes derived from LeIF and TSA of Leishmania donovani evoke anti-leishmania CD8+ T lymphocyte response.

Publications

The potential HLA Class I-restricted epitopes derived from LeIF and TSA of Leishmania donovani evoke anti-leishmania CD8+ T lymphocyte response.

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