Design of multi-epitope peptides containing HLA class-I and class-II-restricted epitopes derived from immunogenic Leishmania proteins, and evaluation of CD4+ and CD8+ T cell responses induced in cured cutaneous leishmaniasis subjects
| Autor: | Yasmine Messaoudi, Elodie Petitdidier, A. Kidar, Karim Aoun, Jean-Loup Lemesre, Julie Pagniez, Sarra Hamrouni, Rym Chamakh-Ayari, Rachel Bras-Gonçalves, Amel Meddeb-Garnaoui |
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| Přispěvatelé: | Laboratoire de Parasitologie Médicale, Biotechnologies et Biomolécules (LR11IPT06), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université de Carthage - University of Carthage, Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bordeaux (UB), Hôpital régional Houcine Bouzaiene [Gafsa], This work was supported by Institut de Recherche pour le développement (IRD). A. M-G is the recipient of ‘Jeune Equipe associée à l’IRD’ (JEAI-VACLeish). |
| Rok vydání: | 2019 |
| Předmět: |
Male
RC955-962 MESH: Flow Cytometry CD8-Positive T-Lymphocytes Epitope Granzymes 0302 clinical medicine Animal Cells Arctic medicine. Tropical medicine Cytotoxic T cell Enzyme-Linked Immunoassays Leishmaniasis Protozoans Innate Immune System MESH: Middle Aged ELISPOT Eukaryota Flow Cytometry MESH: CD8-Positive T-Lymphocytes MESH: Young Adult Cytokines Public aspects of medicine Cellular Types T cell Recombinant Fusion Proteins Immune Cells Immunology Antigens Protozoan Cytotoxic T cells Human leukocyte antigen 03 medical and health sciences Interferon-gamma Antigen MESH: Recombinant Fusion Proteins MESH: Protein Binding Humans Immunoassays MESH: Granzymes MESH: Humans Blood Cells Tumor Necrosis Factor-alpha Histocompatibility Antigens Class I Public Health Environmental and Occupational Health Histocompatibility Antigens Class II Organisms Biology and Life Sciences MESH: Adult Molecular Development MESH: Leishmaniasis Cutaneous Tropical Diseases 030104 developmental biology MESH: Tumor Necrosis Factor-alpha MESH: Female MESH: Antigens Protozoan Developmental Biology 0301 basic medicine CD4-Positive T-Lymphocytes Volunteers MESH: Interleukin-10 Physiology [SDV]Life Sciences [q-bio] Epitopes T-Lymphocyte MESH: Histocompatibility Antigens Class I White Blood Cells Zoonoses Immune Physiology Medicine and Health Sciences Leishmania Vaccines T Cells MESH: CD4-Positive T-Lymphocytes MESH: Enzyme-Linked Immunosorbent Assay Middle Aged Interleukin-10 medicine.anatomical_structure Infectious Diseases Female RA1-1270 Protein Binding Research Article Neglected Tropical Diseases Adult Infectious Disease Control MESH: Interferon-gamma MESH: Leishmania 030231 tropical medicine Leishmaniasis Cutaneous Enzyme-Linked Immunosorbent Assay Biology Research and Analysis Methods MESH: Epitopes T-Lymphocyte Young Adult Immune system medicine Parasitic Diseases Protozoan Infections Cell Biology Molecular biology MESH: Volunteers MESH: Male Parasitic Protozoans Immune System MESH: Histocompatibility Antigens Class II Immunologic Techniques CD8 |
| Zdroj: | PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, 2020, 14 (3), pp.e0008093. ⟨10.1371/journal.pntd.0008093⟩ PLoS Neglected Tropical Diseases, Vol 14, Iss 3, p e0008093 (2020) |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | Human leishmaniasis is a public health problem worldwide for which the development of a vaccine remains a challenge. T cell-mediated immune responses are crucial for protection. Peptide vaccines based on the identification of immunodominant T cell epitopes able to induce T cell specific immune responses constitute a promising strategy. Here, we report the identification of human leukocyte antigen class-I (HLA-I) and -II (HLA-II)-restricted multi-epitope peptides from Leishmania proteins that we have previously described as vaccine candidates. Promastigote Surface Antigen (PSA), LmlRAB (L. major large RAB GTPase) and Histone (H2B) were screened, in silico, for T cell epitopes. 6 HLA-I and 5 HLA-II-restricted multi-epitope peptides, able to bind to the most frequent HLA molecules, were designed and used as pools to stimulate PBMCs from individuals with healed cutaneous leishmaniasis. IFN-γ, IL-10, TNF-α and granzyme B (GrB) production was evaluated by ELISA/CBA. The frequency of IFN-γ-producing T cells was quantified by ELISpot. T cells secreting cytokines and memory T cells were analyzed by flow cytometry. 16 of 25 peptide pools containing HLA-I, HLA-II or HLA-I and -II peptides were able to induce specific and significant IFN-γ levels. No IL-10 was detected. 6 peptide pools were selected among those inducing the highest IFN-γ levels for further characterization. 3/6 pools were able to induce a significant increase of the percentages of CD4+IFN-γ+, CD8+IFN-γ+ and CD4+GrB+ T cells. The same pools also induced a significant increase of the percentages of bifunctional IFN-γ+/TNF-α+CD4+ and/or central memory T cells. We identified highly promiscuous HLA-I and -II restricted epitope combinations from H2B, PSA and LmlRAB proteins that stimulate both CD4+ and CD8+ T cell responses in recovered individuals. These multi-epitope peptides could be used as potential components of a polytope vaccine for human leishmaniasis. Author summary The control of leishmaniasis, a neglected tropical disease of public health importance, caused by protozoan parasites of the genus Leishmania, mainly relies on chemotherapy, which is highly toxic. Currently, there is no vaccine against human leishmaniasis. Peptide-based vaccines consisting of T cell epitopes identified within proteins of interest by epitope predictive algorithms are a promising strategy for vaccine development. Here, we identified multi-epitope peptides composed of HLA-I and -II-restricted epitopes, using immunoinformatic tools, within Leishmania proteins previously described as potential vaccine candidates. We showed that multi-epitope peptides used as pools were able to activate IFN-γ producing CD4+ as well as CD8+ T cells, both required for parasite elimination. In addition, granzyme B-producing CD4+ T cells, bifunctional CD4+ IFN-γ+/TNF-α+ and/or TNF-α+/IL-2+ T cells as well as CD4+ and CD8+ central memory T cells, all involved in Leishmania infection control, were significantly increased in response to multi-epitope peptide stimulation. As far as we know, no study has described the detection of both CD4+ and CD8+ T cell populations in response to stimulation by both HLA-I and II-restricted peptides in humans. The immunogenic HLA-I and -II-restricted multi-epitope peptides identified in this study could constitute potential vaccine candidates against human leishmaniasis. |
| Databáze: | OpenAIRE |
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