Serna Carylinda, Lara Joshua A, Rodrigues Silas P, Marques Alexandre F, Almeida Igor C, Maldonado Rosa A
Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, United States.
Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, United States; Department of Parasitology, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Vaccine. 2014 Jun 12;32(28):3525-32. doi: 10.1016/j.vaccine.2014.04.026. Epub 2014 Apr 30.
Chagas disease, caused by Trypanosoma cruzi, is responsible for producing significant morbidity and mortality throughout Latin America. The disease has recently become a public health concern to nonendemic regions like the U.S. and Europe. Currently there are no fully effective drugs or vaccine available to treat the disease. The mucin-associated surface proteins (MASPs) are glycosylphosphatidylinositol (GPI)-anchored glycoproteins encoded by a multigene family with hundreds of members. MASPs are among the most abundant antigens found on the surface of the infective trypomastigote stage of T. cruzi, thus representing an attractive target for vaccine development. Here we used immunoinformatics to select a 20-mer peptide with several predicted overlapping B-cell, MHC-I, and MHC-II epitopes, from a MASP family member expressed on mammal-dwelling stages of T. cruzi. The synthetic MASP peptide conjugated to keyhole limpet hemocyanin (MASPpep-KLH) was tested in presence or not of an adjuvant (alum, Al) as a vaccine candidate in the C3H/HeNsd murine model of T. cruzi infection. In considerable contrast to the control groups receiving placebo, Al, or KLH alone or the group immunized with MASPpep-KLH/Al, the group immunized with MASPpep-KLH showed 86% survival rate after challenge with a highly lethal dose of trypomastigotes. As evaluated by quantitative real-time polymerase chain reaction, MASPpep-KLH-immunized animals had much lower parasite load in the heart, liver, and spleen than control animals. Moreover, protected animals produced trypanolytic, protective antibodies, and a cytokine profile conducive to resistance against parasite infection. Finally, in vivo depletion of either CD4(+) or CD8(+) T cells indicated that the latter are critical for protection in mice immunized with MASPpep-KLH. In summary, this new peptide-based vaccine with overlapping B- and T-cell epitopes is able to control T. cruzi infection in mice by priming both humoral and cellular immunity.
恰加斯病由克氏锥虫引起，在拉丁美洲导致了严重的发病和死亡情况。该疾病最近已成为美国和欧洲等非流行地区的公共卫生问题。目前尚无完全有效的药物或疫苗可用于治疗该疾病。黏蛋白相关表面蛋白（MASP）是由一个包含数百个成员的多基因家族编码的糖基磷脂酰肌醇（GPI）锚定糖蛋白。MASP是在克氏锥虫感染性锥鞭毛体阶段表面发现的最丰富的抗原之一，因此是疫苗开发的一个有吸引力的靶点。在此，我们利用免疫信息学从在克氏锥虫哺乳动物寄生阶段表达的一个MASP家族成员中选择了一个具有多个预测的重叠B细胞、MHC-I和MHC-II表位的20肽。将与钥孔血蓝蛋白偶联的合成MASP肽（MASPpep-KLH）在有或无佐剂（明矾，Al）存在的情况下作为候选疫苗，在克氏锥虫感染的C3H/HeNsd小鼠模型中进行测试。与接受安慰剂、单独的Al或KLH的对照组或用MASPpep-KLH/Al免疫的组形成显著对比的是，用MASPpep-KLH免疫的组在用高致死剂量的锥鞭毛体攻击后存活率为86%。通过定量实时聚合酶链反应评估，用MASPpep-KLH免疫的动物心脏、肝脏和脾脏中的寄生虫载量比对照动物低得多。此外，受保护的动物产生了溶锥虫保护性抗体以及有利于抵抗寄生虫感染的细胞因子谱。最后，体内去除CD4(+)或CD8(+)T细胞表明，后者对于用MASPpep-KLH免疫的小鼠的保护至关重要。总之这种具有重叠B细胞和T细胞表位的新型基于肽的疫苗能够通过启动体液免疫和细胞免疫来控制小鼠中的克氏锥虫感染。
