Evidence for globally shared, cross-reacting polymorphic epitopes in the pregnancy-associated malaria vaccine candidate VAR2CSA
Evidence for globally shared, cross-reacting polymorphic epitopes in the pregnancy-associated malaria vaccine candidate VAR2CSA
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DOI：
10.1128/iai.01470-07
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发表时间：
2008-04-01
影响因子：
3.1
通讯作者：
Smith, Joseph D.
中科院分区：
文献类型：
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作者：
Avril, Marion;Kulasekara, Bridget R.;Smith, Joseph D.
妊娠相关疟疾(PAM)的特征是胎盘隔离恶性疟原虫感染的红细胞(IES)，并能与硫酸软骨素A(CsA)结合。VAR2CSA是妊娠疟疾疫苗的主要候选者，但其大小(类似于350 kDa)和广泛的多态可能对疫苗开发构成挑战。本研究用毕赤酵母表达的单个VAR2CSA Duffy结合样结构域(DBL)和VAR2csa质粒DNA免疫兔，并在不同的CsA结合寄生虫系上筛选血清。3种重组蛋白(DBL1、DBL3和DBL6)和4种质粒DNA(DBL1、DBL3、DBL5和DBL6)的兔抗体可与同源的FCR3-CsA IES反应。相比之下，DBL4结构域的抗体不能与天然的VAR2CSA蛋白反应，除非它首先被胰酶或胰凝乳酶部分降解。为探讨不同地域CsA结合株之间的抗原性关系，对来自不同大陆来源的4个异源CsA结合系进行了免疫血清筛选。抗体并不针对所有VAR2CSA等位基因中暴露的保守表位；然而，几个DBL结构域的抗血清与具有与同源免疫原相同的多态环路的寄生虫分离株发生交叉反应。这项研究表明，VAR2CSA包含地理上不同的CSA结合线之间共享的常见多态表位。
Pregnancy-associated malaria (PAM) is characterized by the placental sequestration of Plasmodium falciparum-infected erythrocytes (IEs) with the ability to bind to chondroitin sulfate A (CSA). VAR2CSA is a leading candidate for a pregnancy malaria vaccine, but its large size (similar to 350 kDa) and extensive polymorphism may pose a challenge to vaccine development. In this study, rabbits were immunized with individual VAR2CSA Duffy binding-like (DBL) domains expressed in Pichia pastoris or var2csa plasmid DNA and sera were screened on different CSA-binding parasite lines. Rabbit antibodies to three recombinant proteins (DBL1, DBL3, and DBL6) and four plasmid DNAs (DBL1, DBL3, DBL5, and DBL6) reacted with homologous FCR3-CSA IEs. By comparison, antibodies to the DBL4 domain were unable to react with native VAR2CSA protein unless it was first partially proteolyzed with trypsin or chymotrypsin. To investigate the antigenic relationship of geographically diverse CSA-binding isolates, rabbit immune sera were screened on four heterologous CSA-binding lines from different continental origins. Antibodies did not target conserved epitopes exposed in all VAR2CSA alleles; however, antisera to several DBL domains cross-reacted on parasite isolates that had polymorphic loops in common with the homologous immunogen. This study demonstrates that VAR2CSA contains common polymorphic epitopes that are shared between geographically diverse CSA-binding lines.