Leishmania donovani Nucleoside Hydrolase (NH36) Domains Induce T-Cell Cytokine Responses in Human Visceral Leishmaniasis

• Published in: Frontiers in immunology Vol. 8; p. 227
• Main Authors: Barbosa Santos, Micheli Luize, Nico, Dirlei, de Oliveira, Fabrícia Alvisi, Barreto, Aline Silva, Palatnik-de-Sousa, Iam, Carrillo, Eugenia, Moreno, Javier, de Luca, Paula Mello, Morrot, Alexandre, Rosa, Daniela Santoro, Palatnik, Marcos, Bani-Corrêa, Cristiane, de Almeida, Roque Pacheco, Palatnik-de-Sousa, Clarisa Beatriz
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.03.2017
• Subjects: Immunology; nucleoside hydrolase; T cell epitopes; recombinant domains; Leishmania donovani; epitope vaccine design; human visceral leishmaniasis; Leishmania infantum chagasi
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.00227

Development of immunoprotection against visceral leishmaniasis (VL) focused on the identification of antigens capable of inducing a Th1 immune response. Alternatively, antigens targeting the CD8 and T-regulatory responses are also relevant in VL pathogenesis and worthy of being included in a preventive human vaccine. We assessed in active and cured patients and VL asymptomatic subjects the clinical signs and cytokine responses to the nucleoside hydrolase NH36 antigen and its N-(F1), central (F2) and C-terminal (F3) domains. As markers of VL resistance, the F2 induced the highest levels of IFN-γ, IL-1β, and TNF-α and, together with F1, the strongest secretion of IL-17, IL-6, and IL-10 in DTH and cured subjects. F2 also promoted the highest frequencies of CD3 CD4 IL-2 TNF-α IFN-γ , CD3 CD4 IL-2 TNF-α IFN-γ , CD3 CD4 IL-2 TNF-α IFN-γ , and CD3 CD4 IL-2 TNF-α IFN-γ T cells in cured and asymptomatic subjects. Consistent with this, the IFN-γ increase was correlated with decreased spleen (  = -0.428,  = 0.05) and liver sizes (  = -0.428,  = 0.05) and with increased hematocrit counts (  = 0.532,  = 0.015) in response to F1 domain, and with increased hematocrit (  = 0.512, 0.02) and hemoglobin counts (  = 0.434,  = 0.05) in response to F2. Additionally, IL-17 increases were associated with decreased spleen and liver sizes in response to F1 (  = -0.595,  = 0.005) and F2 (  = -0.462,  = 0.04). Conversely, F1 and F3 increased the CD3 CD8 IL-2 TNF-α IFN-γ , CD3 CD8 IL-2 TNF-α IFN-γ , and CD3 CD8 IL-2 TNF-α IFN-γ T cell frequencies of VL patients correlated with increased spleen and liver sizes and decreased hemoglobin and hematocrit values. Therefore, cure and acquired resistance to VL correlate with the CD4 -Th1 and Th-17 T-cell responses to F2 and F1 domains. Clinical VL outcomes, by contrast, correlate with CD8 T-cell responses against F3 and F1, potentially involved in control of the early infection. The -predicted NH36 epitopes are conserved and bind to many HL-DR and HLA and B allotypes. No human vaccine against is available thus far. In this investigation, we identified the NH36 domains and epitopes that induce CD4 and CD8 T cell responses, which could be used to potentiate a human universal T-epitope vaccine against leishmaniasis.