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针对恶性疟原虫妊娠特异性抗原的IgG多重检测

Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens.

作者信息

Fonseca Ana Maria, Quinto Llorenç, Jiménez Alfons, González Raquel, Bardají Azucena, Maculuve Sonia, Dobaño Carlota, Rupérez Maria, Vala Anifa, Aponte John J, Sevene Esperanza, Macete Eusebio, Menéndez Clara, Mayor Alfredo

机构信息

ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.

Graduate Program in Areas of Basic and Applied Biology (GABBA), Universidade do Porto, Porto, Portugal.

出版信息

PLoS One. 2017 Jul 17;12(7):e0181150. doi: 10.1371/journal.pone.0181150. eCollection 2017.

DOI:10.1371/journal.pone.0181150
PMID:28715465
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5513451/
Abstract

BACKGROUND

Pregnant women exposed to Plasmodium falciparum generate antibodies against VAR2CSA, the parasite protein that mediates adhesion of infected erythrocytes to the placenta. There is a need of high-throughput tools to determine the fine specificity of these antibodies that can be used to identify immune correlates of protection and exposure. Here we aimed at developing a multiplex-immunoassay to detect antibodies against VAR2CSA antigens.

METHODS AND FINDINGS

We constructed two multiplex-bead arrays, one composed of 3 VAR2CSA recombinant-domains (DBL3X, DBL5Ɛ and DBL6Ɛ) and another composed of 46 new peptides covering VAR2CSA conserved and semi-conserved regions. IgG reactivity was similar in multiplexed and singleplexed determinations (Pearson correlation, protein array: R2 = 0.99 and peptide array: R2 = 0.87). IgG recognition of 25 out of 46 peptides and all recombinant-domains was higher in pregnant Mozambican women (n = 106) than in Mozambican men (n = 102) and Spanish individuals (n = 101; p<0.05). Agreement of IgG levels detected in cryopreserved plasma and in elutions from dried blood spots was good after exclusion of inappropriate filter papers. Under heterogeneous levels of exposure to malaria, similar seropositivity cutoffs were obtained using finite mixture models applied to antibodies measured on pregnant Mozambican women and average of antibodies measured on pregnant Spanish women never exposed to malaria. The application of the multiplex-bead array developed here, allowed the assessment of higher IgG levels and seroprevalences against VAR2CSA-derived antigens in women pregnant during 2003-2005 than during 2010-2012, in accordance with the levels of malaria transmission reported for these years in Mozambique.

CONCLUSIONS

The multiplex bead-based immunoassay to detect antibodies against selected 25 VAR2CSA new-peptides and recombinant-domains was successfully implemented. Analysis of field samples showed that responses were specific among pregnant women and dependent on the level of exposure to malaria. This platform provides a high-throughput approach to investigating correlates of protection and identifying serological markers of exposure for malaria in pregnancy.

摘要

背景

暴露于恶性疟原虫的孕妇会产生针对VAR2CSA的抗体，VAR2CSA是一种介导受感染红细胞与胎盘黏附的寄生虫蛋白。需要高通量工具来确定这些抗体的精细特异性，以用于识别保护和暴露的免疫相关因素。在此，我们旨在开发一种多重免疫测定法来检测针对VAR2CSA抗原的抗体。

方法与结果

我们构建了两种多重微珠阵列，一种由3个VAR2CSA重组结构域（DBL3X、DBL5Ɛ和DBL6Ɛ）组成，另一种由46个覆盖VAR2CSA保守和半保守区域的新肽组成。在多重和单重测定中，IgG反应性相似（皮尔逊相关性，蛋白阵列：R2 = 0.99，肽阵列：R2 = 0.87）。莫桑比克孕妇（n = 106）对46个肽中的25个以及所有重组结构域的IgG识别率高于莫桑比克男性（n = 102）和西班牙人（n = 101；p<0.05）。在排除不合适的滤纸后，冷冻保存血浆和干血斑洗脱液中检测到的IgG水平一致性良好。在疟疾暴露水平不同的情况下，使用有限混合模型对莫桑比克孕妇检测的抗体以及从未暴露于疟疾的西班牙孕妇检测的抗体平均值进行分析，获得了相似的血清阳性临界值。与莫桑比克这些年份报告的疟疾传播水平一致在此开发的多重微珠阵列的应用显示，2003 - 2005年期间怀孕的女性比2010 - 2012年期间怀孕的女性针对VAR2CSA衍生抗原的IgG水平和血清阳性率更高。

结论

成功实施了基于多重微珠的免疫测定法来检测针对选定的25个VAR2CSA新肽和重组结构域的抗体。对现场样本的分析表明，孕妇的反应具有特异性，并且取决于疟疾暴露水平。该平台为研究保护相关因素和识别妊娠疟疾暴露的血清学标志物提供了一种高通量方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c46/5513451/e76c66e0dfbf/pone.0181150.g006.jpg
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