Laboratório de Biologia e Bioquímica de Leishmania, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
Laboratório de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
Front Immunol. 2014 May 1;5:189. doi: 10.3389/fimmu.2014.00189. eCollection 2014.
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-γ and TNF-α. The F1 vaccine, on the other hand, induced a weaker but significant DTH response and a mild enhancement of IFN-γ and TNF-α 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.
利什曼原虫的核苷水解酶（NH）是利什曼原虫寄生虫之间高度同源的系统发育标记物。在小鼠和犬的疫苗接种中，NH36 诱导针对其 C 末端结构域（F3）的 CD4+T 细胞驱动的保护性反应，从而抵抗莱什曼原虫查加斯氏菌的感染。C 末端和 N 末端结构域疫苗也减少了由莱什曼原虫亚马逊变体引起的足垫病变。我们使用覆盖整个 NH36 序列的重组生成肽和皂苷研究交叉免疫反应的基础，以预防 L.亚马逊变体。F1（氨基酸 1-103）和 F3 肽（氨基酸 199-314）疫苗增强了 IgG 和 IgG2a 抗-NH36 抗体的水平。F3 疫苗诱导最强的 DTH 反应，在挑战后具有最高比例的 NH36 特异性 CD4+和 CD8+T 细胞，并具有最高水平的 IFN-γ和 TNF-α。另一方面，F1 疫苗诱导较弱但具有统计学意义的 DTH 反应，并轻度增强 IFN-γ和 TNF-α水平。用抗 CD4 或 CD8 单克隆抗体进行体内耗竭，揭示了针对 L.亚马逊变体感染的交叉保护是由针对 C 末端结构域的 CD4+T 细胞反应介导的（足垫病变大小减少 75%），随后是针对 NH36 的 N 末端结构域的 CD8+T 细胞反应（足垫病变减少 57%）。两种疫苗都能够诱导长期交叉免疫。NH36 的氨基酸序列与 L.亚马逊变体的 NH A34480 的序列具有 93%的同一性，该序列还显示了在 F1 结构域中针对 CD4+和 CD8+T 细胞的完全保守的预测表位，以及在 F1 和 F3 结构域中针对 CD4+表位的单个氨基酸差异。在 L.亚马逊变体感染模型中，将 C 末端和 N 末端结构域鉴定为 NH36 免疫反应的靶标，为针对利什曼病的双价疫苗的合理开发提供了基础。
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