Antigenic drift in the ligand domain of Plasmodium vivax Duffy binding protein confers resistance to inhibitory antibodies
Antigenic drift in the ligand domain of Plasmodium vivax Duffy binding protein confers resistance to inhibitory antibodies
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DOI：
10.1086/424852
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发表时间：
2004-11-01
影响因子：
6.4
通讯作者：
Adams, JH
中科院分区：
文献类型：
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作者：
VanBuskirk, KM;Cole-Tobian, JL;Adams, JH
达菲结合蛋白（Duffy binding protein， DBP）与其红细胞受体的相互作用对于维持间日疟原虫血期感染至关重要，这使DBP成为一种有吸引力的候选疫苗。富含半胱氨酸的II区是DBP的配体结构域，也是疫苗开发的靶点。有趣的是，在DBP中观察到的大多数等位基因多样性是由于这个受体识别的关键区域的非同义多态性的高比率。与流感血凝素的高变异性类似，DBP配体结构域的这种多态性模式表明，这种变异是逃避抗体中和的一种机制。为了评估dbp等位基因多样性在菌株特异性免疫中的作用，我们检测了抗sal1 dbp血清抑制COS细胞上表达的变异dbp等位基因的红细胞结合功能的能力。我们观察到，与Sal1和PNG-27.16等位基因相比，PNG-7.18等位基因对其红细胞结合活性的免疫抑制明显不敏感。这一结果表明耐药的PNG-7.18的独特多态性是DBP配体上保护性表位的一部分。为了证实这一点，通过位点定向诱变，引入PNG-7.18特有的3个多态性，将Sal1转化为耐药表型。本研究结果表明，连锁多态性对DBP抗原特性具有加性、协同效应。
Interaction of the Duffy binding protein (DBP) with its erythrocyte receptor is critical for maintaining Plasmodium vivax blood-stage infections, making DBP an appealing vaccine candidate. The cysteine-rich region II is the ligand domain of DBP and a target of vaccine development. Interestingly, most of the allelic diversity observed in DBP is due to the high rate of nonsynonymous polymorphisms in this critical domain for receptor recognition. Similar to the hypervariability in influenza hemagglutinin, this pattern of polymorphisms in the DBP ligand domain suggests that this variation is a mechanism to evade antibody neutralization. To evaluate the role that dbp allelic diversity plays in strain-specific immunity, we examined the ability of an anti-Sal1 DBP serum to inhibit the erythrocyte-binding function of variant dbp alleles expressed on COS cells. We observed that the PNG-7.18 allele was significantly less sensitive to immune inhibition of its erythrocyte-binding activity than were the Sal1 and PNG-27.16 alleles. This result suggested that the unique polymorphisms of resistant PNG-7.18 were part of a protective epitope on the DBP ligand. To confirm this, Sal1 was converted to the refractory phenotype by introduction of 3 polymorphisms unique to PNG-7.18, via site-directed mutagenesis. The results of the present study indicate that linked polymorphisms have an additive, synergistic effect on DBP antigenic character.