An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major.
An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major.
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DOI：
10.1371/journal.pntd.0006039
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发表时间：
2017-10
影响因子：
3.8
通讯作者：
Maldonado RA
中科院分区：
文献类型：
--
作者：
Iniguez E;Schocker NS;Subramaniam K;Portillo S;Montoya AL;Al-Salem WS;Torres CL;Rodriguez F;Moreira OC;Acosta-Serrano A;Michael K;Almeida IC;Maldonado RA
利什曼原虫属的原生动物寄生虫引起广泛的临床表现，称为利什曼病，影响全世界数百万人。皮肤利什曼病（CL），由L.主要的，是一种最常见的形式的疾病在旧世界。目前还没有预防性或治疗性的人用疫苗。主要的CL和现有的药物治疗是昂贵的，具有毒副作用，并且已经报道了抗性寄生虫菌株。因此，有必要对该疾病进行进一步的治疗干预。α-吡喃半乳糖基（α-Gal）的末端、非还原性和线性表位在L.主要称为肌醇磷脂。人细胞中不存在这些α-Gal表位，使得这些聚糖具有高度免疫原性，因此可能成为CL疫苗开发的靶点。在这里，我们评估了三种新糖蛋白（NGP），含有人工合成的α-Gal表位共价连接到牛血清白蛋白（BSA），作为针对L.主要，使用α 1，3-半乳糖基转移酶敲除（α1，3GalT-KO）小鼠。这些转基因小鼠与人类相似，在其细胞中不表达非还原性线性α-Gal表位，因此能够产生高水平的抗α-Gal抗体。我们观察到，与对照组相比，Galα（1，6）Galβ-BSA（NGP 5 B）能够将足垫病变的大小显著减小96%，而Galα（1，4）Galβ-BSA（NGP 12 B）或Galα（1，3）Galα-BSA（NGP 17 B）则不能。此外，我们观察到了强大的体液和细胞免疫应答，产生高水平的保护性溶解性抗α-Gal抗体和诱导Th 1细胞因子。我们认为NGP 5 B是一个有吸引力的候选人，为潜在的合成α-半乳糖新糖蛋白为基础的疫苗，针对L。严重感染尽管在世界范围内流行，皮肤利什曼病（CL）仍然在很大程度上被忽视，没有预防或治疗疫苗。在旧大陆，CL主要由利什曼原虫或利什曼原虫引起。热带寄生虫，产生局部皮肤溃疡，往往导致疤痕和社会耻辱。目前，由于冲突和人口流离失所，该疾病在中东已达到高度流行的程度。此外，该地区首选的治疗方法仍然是五价锑剂，这种药物价格昂贵，毒性很大，而目前的病媒控制措施本身不足以阻止疾病传播。因此，针对CL的疫苗将非常有益。先前的研究已经证明糖是对抗利什曼病的有希望的疫苗候选物，因为大多数寄生虫物种具有由免疫原性糖组成的细胞表面涂层，包括线性α-吡喃半乳糖基（α-Gal）表位，其在人类中不存在。在这里，我们开发了一种基于α-Gal的候选疫苗，命名为NGP 5 B。当在转基因小鼠中测试时，这些转基因小鼠像人类一样在其细胞中缺乏α-Gal表位，NGP 5 B能够诱导针对L.主要感染，通过显着减少小鼠足垫病变和寄生虫负担。总之，我们建议NGP 5 B作为一种有希望的预防L.少校
Protozoan parasites from the genus Leishmania cause broad clinical manifestations known as leishmaniases, which affect millions of people worldwide. Cutaneous leishmaniasis (CL), caused by L. major, is one the most common forms of the disease in the Old World. There is no preventive or therapeutic human vaccine available for L. major CL, and existing drug treatments are expensive, have toxic side effects, and resistant parasite strains have been reported. Hence, further therapeutic interventions against the disease are necessary. Terminal, non-reducing, and linear α-galactopyranosyl (α-Gal) epitopes are abundantly found on the plasma membrane glycolipids of L. major known as glycoinositolphospholipids. The absence of these α-Gal epitopes in human cells makes these glycans highly immunogenic and thus potential targets for vaccine development against CL. Here, we evaluated three neoglycoproteins (NGPs), containing synthetic α-Gal epitopes covalently attached to bovine serum albumin (BSA), as vaccine candidates against L. major, using α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mice. These transgenic mice, similarly to humans, do not express nonreducing, linear α-Gal epitopes in their cells and are, therefore, capable of producing high levels of anti-α-Gal antibodies. We observed that Galα(1,6)Galβ-BSA (NGP5B), but not Galα(1,4)Galβ-BSA (NGP12B) or Galα(1,3)Galα-BSA (NGP17B), was able to significantly reduce the size of footpad lesions by 96% in comparison to control groups. Furthermore, we observed a robust humoral and cellular immune response with production of high levels of protective lytic anti-α-Gal antibodies and induction of Th1 cytokines. We propose that NGP5B is an attractive candidate for the study of potential synthetic α-Gal-neoglycoprotein-based vaccines against L. major infection. Despite a worldwide prevalence, cutaneous leishmaniasis (CL) remains largely neglected, with no prophylactic or therapeutic vaccine available. In the Old World, CL is mainly caused by either Leishmania major or L. tropica parasites, which produce localized cutaneous ulcers, often leading to scarring and social stigma. Currently, the disease has reached hyperendemicity levels in the Middle East due to conflict and human displacement. Furthermore, the first choice of treatment in that region continues to be pentavalent antimonials, which are costly and highly toxic, and current vector control measures alone are not sufficient to stop disease transmission. Hence, a vaccine against CL would be very beneficial. Previous studies have demonstrated that sugars are promising vaccine candidates against leishmaniasis, since most parasite species have a cell surface coat composed of immunogenic sugars, including linear α-galactopyranosyl (α-Gal) epitopes, which are absent in humans. Here, we have developed an α-Gal-based vaccine candidate, named NGP5B. When tested in transgenic mice which like humans lack α-Gal epitopes in their cells, NGP5B was able to induce a significant partial protection against L. major infection, by significantly reducing mouse footpad lesions and parasite burden. Altogether, we propose NGP5B as a promising preventive vaccine for CL caused by L. major.
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影响因子：
4.3
作者：
Buskas, T;Li, YH;Boons, GJ
通讯作者：
Boons, GJ
影响因子：
5.7
作者：
Forestier, Claire-Lise;Gao, Qi;Boons, Geert-Jan
通讯作者：
Boons, Geert-Jan
影响因子：
4.1
作者：
ALMEIDA, IC;FERGUSON, MAJ;TRAVASSOS, LR
通讯作者：
TRAVASSOS, LR
影响因子：
3.1
作者：
Coler, RN;Skeiky, YAW;Reed, SG
通讯作者：
Reed, SG
影响因子：
2.9
作者：
Almeida, IC;Covas, DT;Travassos, LR
通讯作者：
Travassos, LR