Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología and Instituto de Estudios de la Inmunidad Humoral Ricardo A. Margni (IDEHU), UBA-CONICET, Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología and Instituto de Microbiología y Parasitología Médica (IMPaM), UBA-CONICET, Buenos Aires, Argentina.
PLoS Negl Trop Dis. 2018 Mar 30;12(3):e0006384. doi: 10.1371/journal.pntd.0006384. eCollection 2018 Mar.
Chagas disease, also known as American Trypanosomiasis, is a chronic parasitic disease caused by the flagellated protozoan Trypanosoma cruzi that affects about 8 million people around the world where more than 25 million are at risk of contracting the infection. Despite of being endemic on 21 Latin-American countries, Chagas disease has become a global concern due to migratory movements. Unfortunately, available drugs for the treatment have several limitations and they are generally administered during the chronic phase of the infection, when its efficacy is considered controversial. Thus, prophylactic and/or therapeutic vaccines are emerging as interesting control alternatives. In this work, we proposed Trypanosoma cruzi 80 kDa prolyl oligopeptidase (Tc80) as a new antigen for vaccine development against Chagas disease.
METHODOLOGY/PRINCIPAL FINDINGS: In a murine model, we analyzed the immune response triggered by different immunization protocols based on Tc80 and evaluated their ability to confer protection against a challenge with the parasite. Immunized mice developed Tc80-specific antibodies which were able to carry out different functions such as: enzymatic inhibition, neutralization of parasite infection and complement-mediated lysis of trypomastigotes. Furthermore, vaccinated mice elicited strong cell-mediated immunity. Spleen cells from immunized mice proliferated and secreted Th1 cytokines (IL-2, IFN-γ and TNF-α) upon re-stimulation with rTc80. Moreover, we found Tc80-specific polyfunctional CD4 T cells, and cytotoxic T lymphocyte activity against one Tc80 MHC-I peptide. Immunization protocols conferred protection against a T. cruzi lethal challenge. Immunized groups showed a decreased parasitemia and higher survival rate compared with non-immunized control mice. Moreover, during the chronic phase of the infection, immunized mice presented: lower levels of myopathy-linked enzymes, parasite burden, electrocardiographic disorders and inflammatory cells.
CONCLUSIONS/SIGNIFICANCE: Considering that an early control of parasite burden and tissue damage might contribute to avoid the progression towards symptomatic forms of chronic Chagas disease, the efficacy of Tc80-based vaccines make this molecule a promising immunogen for a mono or multicomponent vaccine against T. cruzi infection.
恰加斯病，又称美洲锥虫病，是一种由鞭毛原生动物克氏锥虫引起的慢性寄生虫病，全球约有 800 万人受其影响，超过 2500 万人有感染风险。尽管该病在 21 个拉丁美洲国家流行，但由于移民流动，它已成为全球关注的问题。不幸的是，现有的治疗药物存在多种局限性，通常在感染的慢性期使用，而此时其疗效存在争议。因此，预防性和/或治疗性疫苗作为有前途的控制替代方案而出现。在这项工作中，我们提出了克氏锥虫 80kDa 脯氨酰寡肽酶（Tc80）作为一种新的抗原，用于开发针对恰加斯病的疫苗。
方法/主要发现：在小鼠模型中，我们分析了基于 Tc80 的不同免疫方案引发的免疫反应，并评估了它们抵御寄生虫感染的能力。免疫小鼠产生了 Tc80 特异性抗体，这些抗体能够发挥不同的功能，如：酶抑制、中和寄生虫感染和补体介导的锥虫溶解。此外，接种疫苗的小鼠还引发了强烈的细胞免疫。用 rTc80 再刺激后，来自免疫小鼠的脾细胞增殖并分泌 Th1 细胞因子（IL-2、IFN-γ 和 TNF-α）。此外，我们发现了 Tc80 特异性多功能 CD4 T 细胞和针对 Tc80 MHC-I 肽的细胞毒性 T 淋巴细胞活性。免疫方案赋予了针对致命性克氏锥虫感染的保护。与未免疫的对照组小鼠相比，免疫组的寄生虫血症和存活率降低。此外，在感染的慢性期，免疫小鼠表现出：肌病相关酶、寄生虫负荷、心电图紊乱和炎症细胞水平降低。
结论/意义：鉴于早期控制寄生虫负荷和组织损伤可能有助于避免向慢性恰加斯病的症状形式发展，基于 Tc80 的疫苗的功效使该分子成为针对克氏锥虫感染的单或多组分疫苗的有前途的免疫原。
