The NTS-DBL2X Region of VAR2CSA Induces Cross-Reactive Antibodies That Inhibit Adhesion of Several Plasmodium falciparum Isolates to Chondroitin Sulfate A
The NTS-DBL2X Region of VAR2CSA Induces Cross-Reactive Antibodies That Inhibit Adhesion of Several Plasmodium falciparum Isolates to Chondroitin Sulfate A
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DOI：
10.1093/infdis/jir499
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发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Ndam, Nicaise Tuikue
中科院分区：
文献类型：
--
作者：
Bigey, Pascal;Gnidehou, Sedami;Ndam, Nicaise Tuikue
背景资料。通过VAR2CSA与硫酸软骨素A结合，VAR2CSA是一种表达在感染红细胞上的寄生虫蛋白，允许胎盘隔离感染恶性疟原虫的红细胞。这会导致母亲贫血、死产和胎儿宫内发育迟缓等严重后果。后者显然与婴儿发病率和死亡率的增加有关。获得性抗VAR2CSA抗体与改善妊娠结局有关，这表明疫苗可以预防这种综合征。然而，在大的VAR2CSA蛋白中寻找功能重要的区域是困难的。利用基因免疫技术，在小鼠和兔体内制备了针对VAR2CSA重叠片段的多克隆抗血清。在实验室适应的寄生虫系和表达VAR2CSA的野外分离株上，评估了疟疾暴露孕妇诱导的抗血清和从血浆中纯化的特异性抗体的黏附抑制能力。采用竞争酶联免疫吸附试验(EL ISA)分析动物体内诱导的抗体与免疫多胎自然获得的抗体在功能上的相似性。针对直至DBL2X的N末端序列(NTS-DBL2X)的抗体有效地阻止寄生虫与硫酸软骨素A的黏附，其方式类似于针对整个VAR2CSA胞外区的抗体。有趣的是，自然获得的抗体和那些通过接种NTS-DBL2X疫苗诱导的抗体针对重叠的菌株-超越的抗黏附表位。这项研究强调了在开发针对胎盘疟疾的保护性疫苗方面取得的重要进展。
Background. Binding to chondroitin sulfate A by VAR2CSA, a parasite protein expressed on infected erythrocytes, allows placental sequestration of Plasmodium falciparum-infected erythrocytes. This leads to severe consequences such as maternal anemia, stillbirths, and intrauterine growth retardation. The latter has been clearly associated to increased morbidity and mortality of the infants. Acquired anti-VAR2CSA antibodies have been associated with improved pregnancy outcomes, suggesting a vaccine could prevent the syndrome. However, identifying functionally important regions in the large VAR2CSA protein is difficult.Methods. Using genetic immunization, we raised polyclonal antisera against overlapping segments of VAR2CSA in mice and rabbits. The adhesion-inhibition capacities of induced antisera and of specific antibodies purified from plasma of malaria-exposed pregnant women were assessed on laboratory-adapted parasite lines and field isolates expressing VAR2CSA. Competition enzyme-linked immunosorbent assay (ELISA) was employed to analyze functional resemblance between antibodies induced in animals and those naturally acquired by immune multigravidae.Results. Antibodies targeting the N-terminal sequence (NTS) up to DBL2X (NTS-DBL2X) efficiently blocked parasite adhesion to chondroitin sulfate A in a manner similar to that of antibodies raised against the entire VAR2CSA extracellular domain. Interestingly, naturally acquired antibodies and those induced by vaccination against NTS-DBL2X target overlapping strain-transcendent anti-adhesion epitopes.Conclusions. This study highlights an important step achieved toward development of a protective vaccine against placental malaria.