Functional Characterization and Comparison of Plasmodium falciparum Proteins as Targets of Transmission-blocking Antibodies.
Functional Characterization and Comparison of Plasmodium falciparum Proteins as Targets of Transmission-blocking Antibodies.
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DOI：
10.1074/mcp.ra117.000036
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Biswas S
中科院分区：
文献类型：
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作者：
Nikolaeva D;Illingworth JJ;Miura K;Alanine DGW;Brian IJ;Li Y;Fyfe AJ;Da DF;Cohuet A;Long CA;Draper SJ;Biswas S
疟疾病原体恶性疟原虫继续逃避控制努力。尽管有多个疟原虫性阶段转录组和蛋白质组数据集，但尚未进行合理的筛选来识别用于阻断传播疫苗（TBV）开发的候选抗原。我们展示了如何使用理性筛选和比较功能评估来识别恶性疟原虫传播途径的蛋白质并建立强大的临床前 TBV 管道。重点描述了恶性疟原虫性阶段的 12 种蛋白质作为可能的 TBV 靶点的特征。异源表达的重组蛋白概括了天然寄生虫表位。当针对疟疾流行的布基纳法索和马里个体的血清进行测试时，一些重组蛋白表现出免疫反应性。针对抗原烯醇化酶的纯化 IgG 可适度抑制蚊子中肠中的寄生虫发育。恶性疟原虫疟疾继续逃避控制努力，利用高度专业化的性阶段在人类宿主和蚊媒之间传播感染。在疫苗接种模型中，当蚊子血粉中摄入针对性阶段抗原的抗体时，可以抑制中肠中的寄生虫生长，从而阻止传播。尽管有多个疟原虫性阶段转录组和蛋白质组数据集，但尚未进行合理的筛选来识别用于阻断传播疫苗（TBV）开发的候选抗原。这项研究将恶性疟原虫性阶段的 12 种蛋白质描述为可能的 TBV 靶标。重组蛋白在哺乳动物 HEK293 细胞系统中异源表达为全长胞外域。通过间接荧光测定评估，这些蛋白质再现了天然寄生虫表位，并且当针对生活在疟疾流行的布基纳法索和马里的个体的血清进行测试时，其中一部分表现出免疫反应性。通过离体标准膜喂养测定，针对蚊子阶段寄生虫抗原烯醇化酶产生的纯化 IgG 表明对蚊子中肠中寄生虫的发育有一定的抑制作用。研究结果支持使用合理筛选和比较功能评估来识别恶性疟原虫传播途径的蛋白质并建立强大的临床前 TBV 管道。
The malaria agent Plasmodium falciparum continues to evade control efforts. Despite multiple datasets for the Plasmodium sexual-stage transcriptome and proteome, there have been no rational screens to identify candidate antigens for transmission-blocking vaccine (TBV) development. We demonstrate the use of rational screens and comparative functional assessments in identifying proteins of the P. falciparum transmission pathway and establishing a robust pre-clinical TBV pipeline. Highlights Characterization of 12 proteins from across the P. falciparum sexual-stages as possible TBV targets. Heterologously expressed recombinant proteins recapitulate native parasite epitopes. Some recombinant proteins exhibit immunoreactivity when tested against sera from individuals from malaria-endemic Burkina Faso and Mali. Purified IgG against the antigen enolase moderately inhibits parasite development in the mosquito midgut. Plasmodium falciparum malaria continues to evade control efforts, utilizing highly specialized sexual-stages to transmit infection between the human host and mosquito vector. In a vaccination model, antibodies directed to sexual-stage antigens, when ingested in the mosquito blood meal, can inhibit parasite growth in the midgut and consequently arrest transmission. Despite multiple datasets for the Plasmodium sexual-stage transcriptome and proteome, there have been no rational screens to identify candidate antigens for transmission-blocking vaccine (TBV) development. This study characterizes 12 proteins from across the P. falciparum sexual-stages as possible TBV targets. Recombinant proteins are heterologously expressed as full-length ectodomains in a mammalian HEK293 cell system. The proteins recapitulate native parasite epitopes as assessed by indirect fluorescence assay and a proportion exhibits immunoreactivity when tested against sera from individuals living in malaria-endemic Burkina Faso and Mali. Purified IgG generated to the mosquito-stage parasite antigen enolase demonstrates moderate inhibition of parasite development in the mosquito midgut by the ex vivo standard membrane feeding assay. The findings support the use of rational screens and comparative functional assessments in identifying proteins of the P. falciparum transmission pathway and establishing a robust pre-clinical TBV pipeline.