Evidence for erythrocyte-binding antigen 175 as a component of a ligand-blocking blood-stage malaria vaccine
Evidence for erythrocyte-binding antigen 175 as a component of a ligand-blocking blood-stage malaria vaccine
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DOI：
10.1073/pnas.1104050108
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发表时间：
2011-05-03
影响因子：
11.1
通讯作者：
Miller, Louis H.
中科院分区：
文献类型：
--
作者：
Jiang, Lubin;Gaur, Deepak;Miller, Louis H.
病原体用来侵入其靶细胞的配体通常被证明是疫苗开发的良好靶点。然而，恶性疟原虫具有介导红细胞侵入的冗余配体。开发成功的配体阻断疟疾疫苗的第一个要求是证明针对每个配体诱导的抗体可以阻断具有多态性序列的寄生虫的红细胞侵入。由于恶性疟原虫在红细胞侵入中的冗余，需要在人造条件下研究每种配体，其中寄生虫侵入在其使用替代途径方面受到限制。在这里，我们调查的红细胞结合抗原175（EBA-175），寄生虫的配体结合血型糖蛋白A上的唾液酸，在入侵的红细胞由10个恶性疟原虫克隆的条件下，其中入侵部分限于EBA-175-血型糖蛋白A途径，使用胰凝乳蛋白酶处理的红细胞的作用。我们表明，唾液酸非依赖性和唾液酸依赖性途径侵入红细胞的能力需要EBA-175-血型糖蛋白A途径的红细胞侵入。重要的是，针对来自3D 7克隆的EBA-175的区域II的抗体阻断了所研究的所有寄生虫克隆（包括文献中描述的具有多种不同突变的那些寄生虫克隆）对胰凝乳蛋白酶处理的红细胞的侵袭> 50%。一个例外是FCR 3，其具有与3D 7相似的序列，但对胰凝乳蛋白酶处理的红细胞的侵袭仅抑制30%，表明胰凝乳蛋白酶处理的红细胞的侵袭的替代途径。我们的研究结果表明，抗体EBA-175的区域II，作为一个组成部分的配体阻断疟疾疫苗，在很大程度上不受多态性EBA-175。
The ligands that pathogens use to invade their target cells have often proven to be good targets for vaccine development. However, Plasmodium falciparum has redundant ligands that mediate invasion of erythrocytes. The first requirement for the development of a successful ligand-blocking malaria vaccine is the demonstration that antibodies induced to each ligand can block the erythrocyte invasion of parasites with polymorphic sequences. Because of P. falciparum's redundancy in erythrocyte invasion, each ligand needs to be studied under artificial conditions in which parasite invasion is restricted in its use of alternative pathways. Here we investigate the role of erythrocyte-binding antigen 175 (EBA-175), a parasite ligand that binds to sialic acid on glycophorin A, in the invasion of erythrocytes by 10 P. falciparum clones under conditions in which invasion is partially limited to the EBA-175-glycophorin A pathway, using chymotrypsin-treated erythrocytes. We show that the ability to invade erythrocytes for both sialic acid-independent and sialic acid-dependent pathways requires the EBA-175-glycophorin A pathway for erythrocyte invasion. Importantly, antibodies against region II of EBA-175 from the 3D7 clone blocked invasion of chymotrypsin-treated erythrocytes by > 50% by all parasite clones studied, including those with multiple different mutations described in the literature. The one exception was FCR3, which had a similar sequence to 3D7 but only 30% inhibition of invasion of chymotrypsin-treated erythrocytes, indicating alternative pathways for invasion of chymotrypsin-treated erythrocytes. Our findings suggest that antibodies to region II of EBA-175, as one component of a ligand-blocking malaria vaccine, are largely unaffected by polymorphism in EBA-175.