Induction of Adhesion-Inhibitory Antibodies against Placental Plasmodium falciparum Parasites by Using Single Domains of VAR2CSA
Induction of Adhesion-Inhibitory Antibodies against Placental Plasmodium falciparum Parasites by Using Single Domains of VAR2CSA
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DOI：
10.1128/iai.00159-09
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发表时间：
2009-06-01
影响因子：
3.1
通讯作者：
Salanti, Ali
中科院分区：
文献类型：
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作者：
Nielsen, Morten A.;Pinto, Vera V.;Salanti, Ali
在流行地区，与妊娠有关的疟疾是造成产妇贫血、死产和低体重儿分娩的重要原因。该综合征是由恶性疟原虫感染的红细胞在胎盘中的积累引起的，通过红细胞上表达的称为变体表面抗原2-硫酸软骨素A（VAR 2CSA）的寄生虫蛋白与合胞体滋养层上的CSA之间的相互作用介导。VAR 2CSA是由六个Duffy结合样（DBL）结构域组成的大型多态性蛋白，并且由于目前对重组蛋白生产的限制，不可能生产完整的VAR 2CSA重组蛋白。此外，多态性的存在还提出了一个问题：定义可引发广泛保护性抗体的VAR 2CSA抗原是否可行。因此，疫苗开发的挑战是确定诱导抑制不同寄生虫株CSA结合的抗体的分子的较小部分。在这项研究中，我们产生了一个大面板的VAR 2CSA蛋白质和提高针对这些抗原的抗体。我们表明，针对DBL 4结构域的抗体有效地抑制寄生虫结合。由于抑制作用不限于同源寄生虫株，因此基于单个VAR 2CSA DBL结构域的保护性疟疾疫苗似乎是可行的。
In areas of endemicity pregnancy-associated malaria is an important cause of maternal anemia, stillbirth, and delivery of low-birth-weight children. The syndrome is precipitated by the accumulation of Plasmodium falciparum-infected erythrocytes in the placenta, mediated through an interaction between a parasite protein expressed on erythrocytes named variant surface antigen 2-chondroitin sulfate A (VAR2CSA) and CSA on syncytiotrophoblasts. VAR2CSA is a large polymorphic protein consisting of six Duffy binding-like (DBL), domains and with current constraints on recombinant protein production it is not possible to produce entire VAR2CSA recombinant proteins. Furthermore, the presence of polymorphisms has raised the question of whether it is feasible to define VAR2CSA antigens eliciting broadly protective antibodies. Thus, the challenge for vaccine development is to define smaller parts of the molecule which induce antibodies that inhibit CSA binding of different parasite strains. In this study, we produced a large panel of VAR2CSA proteins and raised antibodies against these antigens. We show that antibodies against the DBL4 domain effectively inhibit parasite binding. As the inhibition was not limited to homologous parasite strains, it seems feasible to base a protective malaria vaccine on a single VAR2CSA DBL domain.