Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection.
Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection.
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DOI：
10.1038/s41541-017-0010-z
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发表时间：
2017
期刊：
影响因子：
9.2
通讯作者：
Malchiodi EL
中科院分区：
文献类型：
--
作者：
Sanchez Alberti A;Bivona AE;Cerny N;Schulze K;Weißmann S;Ebensen T;Morales C;Padilla AM;Cazorla SI;Tarleton RL;Guzmán CA;Malchiodi EL
克氏锥虫寄生虫是恰加斯病的病原体，恰加斯病是一种可能危及生命的感染，是拉丁美洲的一个主要卫生问题。这种原生动物的几个特点导致缺乏有效的疫苗，其中包括：其沉默侵袭机制，克氏T.抗原冗余和无保护的免疫优势。考虑到这些问题，我们设计了Traspain，这是一种嵌合抗原，专门用于展示关键寄生分子的多价结构域，并结合c-di-AMP刺激STING途径作为一种新的预防策略。该制剂被证明对启动功能性体液反应和病原体特异性CD8+和CD4+ T细胞有效，与Th1/Th17偏倚兼容。有趣的是，在整个感染过程中评估的疫苗有效性显示，在不同的概念验证分析中，寄生虫载量和慢性炎症有所减少。总之，这种方法是一种很有前途的对抗寄生虫慢性感染的工具。一种寄生虫蛋白的混合可能是针对尚无法治疗的恰加斯病慢性期的第一种有效疫苗。这种疾病是由克氏锥虫（T. cruzi）寄生虫造成的，是世界上感染性心脏炎症的主要原因，使拉丁美洲六分之一的人口面临感染风险。由阿根廷布宜诺斯艾利斯大学的Emilio Malchiodi领导的国际合作者构建了一种疫苗（称为“Traspain”），该疫苗由关键的克氏t型病毒蛋白和一种新的“佐剂”组成，旨在通过激活炎症反应来促进疫苗的效力。嵌合体和佐剂的组合引起了有希望的免疫反应，也显示出防止慢性感染引起的组织损伤的能力。像Traspain这样的多组分疫苗为研究抗慢性寄生虫感染的疫苗提供了一个有吸引力的方向。
The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a potentially life-threatening infection that represents a major health problem in Latin America. Several characteristics of this protozoan contribute to the lack of an effective vaccine, among them: its silent invasion mechanism, T. cruzi antigen redundancy and immunodominance without protection. Taking into account these issues, we engineered Traspain, a chimeric antigen tailored to present a multivalent display of domains from key parasitic molecules, combined with stimulation of the STING pathway by c-di-AMP as a novel prophylactic strategy. This formulation proved to be effective for the priming of functional humoral responses and pathogen-specific CD8+ and CD4+ T cells, compatible with a Th1/Th17 bias. Interestingly, vaccine effectiveness assessed across the course of infection, showed a reduction in parasite load and chronic inflammation in different proof of concept assays. In conclusion, this approach represents a promising tool against parasitic chronic infections. An amalgamation of parasitic proteins may be the first effective vaccine against the as yet untreatable chronic phase of Chagas disease. The infliction, caused by the parasite Trypanosoma cruzi (T. cruzi), is the world’s leading cause of infectious cardiac inflammation and puts one-sixth of the population of Latin America at risk of infection. International collaborators led by Emilio Malchiodi, of the University of Buenos Aires, Argentina, constructed a vaccine (dubbed ‘Traspain’) comprised of key T. cruzi proteins alongside a novel ‘adjuvant’—designed to promote the efficacy of a vaccine by activating inflammatory responses. The chimera and adjuvant combination elicited a promising immune response and also showed the capacity to prevent tissue damage caused by chronic infection. Multi-part vaccines such as Traspain offer an attractive direction for research into vaccines against chronic parasitic infections.