Structural basis of antigenic escape of a malaria vaccine candidate
Structural basis of antigenic escape of a malaria vaccine candidate
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DOI：
10.1073/pnas.0701464104
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发表时间：
2007-07-24
影响因子：
11.1
通讯作者：
Lanar, David E.
中科院分区：
文献类型：
--
作者：
Dutta, Sheetij;Lee, Seung Yeon;Lanar, David E.
抗疟疾疫苗候选物顶端膜抗原-1（AMA-1）的抗体可以抑制裂殖子侵入RBC，但抗原多样性可能会影响疫苗效力。我们假设，多态性位点位于抑制性表位的功能作为抗原逃逸残基（AER）。通过使用抗原逃逸的体外模型，确定3D7 AMA-1疫苗的24个多态性位点的抑制贡献。位于结构域1内的13个多态性的AER簇具有最高的抑制作用。在该AER簇内，抗体主要针对位于非螺旋环上的五个多态性残基。第二个重要的AER簇定位于结构域2。结构域3多态性增强了结构域2 AER簇的抑制作用。重要的是，AER簇可以分裂，使得含有FVO的结构域1和3D7的结构域2 + 3的嵌合体产生显示出对两种疫苗株的类似高水平抑制的抗血清。这种嵌合蛋白的抗体也能抑制寄生虫的不相关菌株。菌株间AER嵌合体可以是将两种AMA-1菌株的抑制性表位整合到单一蛋白质中的一种方式。AER簇与保守的结构元件非常接近：疏水槽和C-末端蛋白水解加工位点。这一发现使我们假设存在从抗AMA-1的抗原逃逸的保守结构基础。基因分型高影响AER可能是有用的AMA-1菌株的抑制组分类和检测等位基因的AMA-1疫苗在现场的影响。
Antibodies against the malaria vaccine candidate apical membrane antigen-1 (AMA-1) can inhibit invasion of merozoites into RBC, but antigenic diversity can compromise vaccine efficacy. We hypothesize that polymorphic sites located within inhibitory epitopes function as antigenic escape residues (AER). By using an in vitro model of antigenic escape, the inhibitory contribution of 24 polymorphic sites of the 3D7 AMA-1 vaccine was determined. An AER cluster of 13 polymorphisms, located within domain 1, had the highest inhibitory contribution. Within this AER cluster, antibodies primarily targeted five polymorphic residues situated on an ahelical loop. A second important AER cluster was localized to domain 2. Domain 3 polymorphisms enhanced the inhibitory contribution of the domain 2 AER cluster. Importantly, the AER clusters could be split, such that chimeras containing domain 1 of FVO and domain 2 + 3 of 3D7 generated antisera that showed similarly high level inhibition of the two vaccine strains. Antibodies to this chimeric protein also inhibited unrelated strains of the parasite. Interstrain AER chimeras can be a way to incorporate inhibitory epitopes of two AMA-1 strains into a single protein. The AER clusters map in close proximity to conserved structural elements: the hydrophobic trough and the C-terminal proteolytic processing site. This finding led us to hypothesize that a conserved structural basis of antigenic escape from anti-AMA-1 exists. Genotyping high-impact AER may be useful for classifying AMA-1 strains into inhibition groups and to detect allelic effects of an AMA-1 vaccine in the field.