Background Plasmodium falciparum-infected red blood cells (iRBCs) bind and sequester in deep vascular beds, causing malaria-related disease and death. In pregnant women, VAR2CSA binds to chondroitin sulfate A (CSA) and mediates placental sequestration, making it the major placental malaria (PM) vaccine target. Methods In this study, we characterize an invariant protein associated with PM called P falciparum chondroitin sulfate A ligand (PfCSA-L). Results Recombinant PfCSA-L binds both placental CSA and VAR2CSA with nanomolar affinity, and it is coexpressed on the iRBC surface with VAR2CSA. Unlike VAR2CSA, which is anchored by a transmembrane domain, PfCSA-L is peripherally associated with the outer surface of knobs through high-affinity protein-protein interactions with VAR2CSA. This suggests that iRBC sequestration involves complexes of invariant and variant surface proteins, allowing parasites to maintain both diversity and function at the iRBC surface. Conclusions The PfCSA-L is a promising target for intervention because it is well conserved, exposed on infected cells, and expressed and localized with VAR2CSA.

中文翻译：

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在恶性疟原虫感染的红细胞上与 VAR2CSA 共定位的不变蛋白与硫酸软骨素 A 结合

背景 受恶性疟原虫感染的红细胞 (iRBC) 结合并隔离在深层血管床中，导致疟疾相关疾病和死亡。在孕妇中，VAR2CSA 与硫酸软骨素 A (CSA) 结合并介导胎盘隔离，使其成为主要的胎盘疟疾 (PM) 疫苗靶点。方法 在这项研究中，我们描述了一种与 PM 相关的不变蛋白，称为恶性疟原虫硫酸软骨素 A 配体 (PfCSA-L)。结果重组 PfCSA-L 以纳摩尔级的亲和力结合胎盘 CSA 和 VAR2CSA，并与 VAR2CSA 在 iRBC 表面共表达。与由跨膜结构域锚定的 VAR2CSA 不同，PfCSA-L 通过与 VAR2CSA 的高亲和力蛋白质-蛋白质相互作用与结节的外表面外围相关。这表明 iRBC 隔离涉及不变和变体表面蛋白的复合物，允许寄生虫在 iRBC 表面保持多样性和功能。结论 PfCSA-L 是一个有希望的干预靶点，因为它保存完好，暴露在感染细胞上，并用 VAR2CSA 表达和定位。