Immunogenicity of Duffy binding-like domains that bind chondroitin sulfate A and protection against pregnancy-associated malaria
Immunogenicity of Duffy binding-like domains that bind chondroitin sulfate A and protection against pregnancy-associated malaria
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DOI：
10.1128/iai.00481-06
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发表时间：
2006-10-01
影响因子：
3.1
通讯作者：
Chitnis, Chetan E.
中科院分区：
文献类型：
--
作者：
Bir, Nivedita;Yazdani, Syed Shams;Chitnis, Chetan E.
胎盘中疟原虫感染红细胞的隔离与妊娠相关疟疾（PAM）的病理结果有关。在胎盘中隔离的恶性疟原虫分离物主要结合硫酸软骨素A（CSA）。在妊娠期间接触疟疾后，地方病地区的妇女产生免疫力，因此多次妊娠的妇女对PAM的敏感性低于孕妇。对PAM的保护性免疫与识别多种CSA结合的胎盘恶性疟原虫分离株的抗体的产生有关。这种保护性抗体识别的表位尚未确定，但可能位于保守的Duffy结合样（DBL）结构域，由var基因编码，结合CSA。用由var1CSA编码的CSA结合DBL3 γ结构域免疫小鼠可产生交叉反应性抗体，这些抗体识别不同的CSA结合恶性疟原虫分离株，并阻断它们与流动下胎盘冷冻切片的结合。然而，CSA结合分离株主要表达var2CSA，其不编码任何DBL γ结构域。在这里，我们证明了抗体提出的DBL3 γ编码的var1CSA交叉反应的CSA结合域，DBL3X，编码的var2CSA之一。这解释了此处和之前的矛盾观察，即抗rDBL3 γ血清识别CSA结合分离株，并为不同CSA结合DBL结构域中存在保守的交叉反应性表位提供了证据。CSA结合DBL结构域内的这种交叉反应性表位可以形成提供针对PAM的保护的疫苗的基础。
Sequestration of Plasmodium fakiparum-infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM). P. falciparum isolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSA-binding, placental P. falciparum isolates. The epitopes recognized by such protective antibodies have not been identified but are likely to lie in conserved Duffy binding-like (DBL) domains, encoded by var genes, that bind CSA. Immunization of mice with the CSA-binding DBL3 gamma domain encoded by var1CSA elicits cross-reactive antibodies that recognize diverse CSA-binding P. falciparum isolates and block their binding to placental cryosections under flow. However, CSA-binding isolates primarily express var2CSA, which does not encode any DBL gamma domains. Here, we demonstrate that antibodies raised against DBL3 gamma encoded by var1CSA cross-react with one of the CSA-binding domains, DBL3X, encoded by var2CSA. This explains the paradoxical observation made here and earlier that anti-rDBL3 gamma sera recognize CSA-binding isolates and provides evidence for the presence of conserved, cross-reactive epitopes in diverse CSA-binding DBL domains. Such cross-reactive epitopes within CSA-binding DBL domains can form the basis for a vaccine that provides protection against PAM.