Structural insight into epitopes in the pregnancy-associated malaria protein VAR2CSA.
Structural insight into epitopes in the pregnancy-associated malaria protein VAR2CSA.
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DOI：
10.1371/journal.ppat.0040042
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发表时间：
2008-02-08
期刊：
影响因子：
6.7
通讯作者：
Salanti, Ali
中科院分区：
文献类型：
--
作者：
Andersen, Pernille;Nielsen, Morten A.;Resende, Mafalda;Rask, Thomas S.;Dahlback, Madeleine;Theander, Thor;Lund, Ole;Salanti, Ali
妊娠相关性疟疾是由恶性疟原虫疟原虫与胎盘中硫酸软骨素A特异性结合引起的。这种对寄生虫的隔离是婴儿出生体重低和母亲贫血的主要原因。VAR2CSA是PfEMP1家族的多态性多结构域蛋白，是CSA结合的主要寄生虫配体，鉴定保护性抗体表位对VAR2CSA疫苗的开发至关重要。试图确定VAR2CSA或其结构域的晶体结构尚未成功。在这项研究中，我们提出了每个VAR2CSA DBL结构域的3D模型，我们发现VAR2CSA域间2和PfEMP1 CIDR结构域的褶皱区域似乎与EBA-175和Pkα-DBL褶皱同源。这表明ID2可能是一个功能域。我们还通过多肽阵列实验，比较含有抗VAR2CSA抗体的血浆与天然VAR2CSA孵育前后的反应性，确定了天然VAR2CSA表面存在的VAR2CSA区域。通过这种方法，我们确定了与感染红细胞上表达的天然分子反应的抗体靶向的保守的VAR2CSA区域。通过将数据映射到DBL模型，我们提出证据表明S1+S2 DBL子域在大多数域中通常是表面暴露的，而S3子域在原生VAR2CSA中较少暴露。这些结果是了解与csa结合的感染红细胞表面的VAR2CSA结构的重要一步。生活在恶性疟原虫高传播地区的个人随着时间的推移会获得对疟疾的免疫力，成年人患严重疾病的风险显著降低。然而，孕妇是一个重要的例外，她们在怀孕期间更容易感染疟疾。这种所谓的妊娠相关疟疾（PAM）对母亲和儿童都有严重后果，一种疫苗每年可以挽救数十万人的生命。PAM是由恶性疟原虫感染的红细胞与胎盘中的受体结合引起的。通过与胎盘组织结合，寄生虫避免了通过脾脏被过滤，否则它们会被杀死。介导胎盘结合的蛋白是一种非常大的多结构域变异蛋白，名为VAR2CSA。通过对患有PAM的女性的VAR2CSA和抗体试剂进行结构建模，我们发现抗体倾向于在单个VAR2CSA结构域的一侧的相似区域结合。此外，我们发现这种变异蛋白的高度保守部分可以被抗体接触到。这一发现与流行病学数据相关，这些数据显示，妇女对PAM获得免疫力相对较快，因此这些表位的鉴定是朝着保护性疫苗迈出的重要一步。
Pregnancy-associated malaria is caused by Plasmodium falciparum malaria parasites binding specifically to chondroitin sulfate A in the placenta. This sequestration of parasites is a major cause of low birth weight in infants and anemia in the mothers. VAR2CSA, a polymorphic multi-domain protein of the PfEMP1 family, is the main parasite ligand for CSA binding, and identification of protective antibody epitopes is essential for VAR2CSA vaccine development. Attempts to determine the crystallographic structures of VAR2CSA or its domains have not been successful yet. In this study, we propose 3D models for each of the VAR2CSA DBL domains and we show that regions in the fold of VAR2CSA inter-domain 2 and a PfEMP1 CIDR domain seem to be homologous to the EBA-175 and Pkα-DBL fold. This suggests that ID2 could be a functional domain. We also identify regions of VAR2CSA present on the surface of native VAR2CSA by comparing reactivity of plasma containing anti-VAR2CSA antibodies in peptide array experiments before and after incubation with native VAR2CSA. By this method we identify conserved VAR2CSA regions targeted by antibodies that react with the native molecule expressed on infected erythrocytes. By mapping the data onto the DBL models we present evidence suggesting that the S1+S2 DBL sub-domains are generally surface-exposed in most domains, whereas the S3 sub-domains are less exposed in native VAR2CSA. These results comprise an important step towards understanding the structure of VAR2CSA on the surface of CSA-binding infected erythrocytes. Individuals living in areas with high Plasmodium falciparum transmission acquire immunity to malaria over time and adults have markedly reduced risk of getting severe disease. However, pregnant women constitute an important exception, and they become more susceptible to malaria during pregnancy. This so called pregnancy-associated malaria (PAM) has severe consequences for both mother and child, and a vaccine would save hundreds of thousands of lives each year. PAM is caused by P. falciparum–infected red blood cells that bind to receptors in the placenta. By binding to the placental tissue, the parasites avoid being filtered though the spleen where they would have been killed. The protein mediating this placental binding is a very large multidomain and variant protein named VAR2CSA. Using structural modeling of VAR2CSA and antibody reagents from women who have had PAM, we show that antibodies tend to bind in similar regions, on one side of the individual VAR2CSA domains. In addition, we show that highly conserved parts of this variant protein are accessible for antibodies. This finding correlates with epidemiological data showing that woman acquire immunity towards PAM relatively fast, and the identification of these epitopes is thus a major step towards a protective vaccine.
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