丹麦哥本哈根大学Thomas Lavstsen、Louise Turner和美国德克萨斯大学Evelien M. Bunnik合作的最新研究，报道了靶向严重疟疾毒力蛋白的广泛抑制抗体。相关论文于2024年11月20日发表在《自然》杂志上。

疟疾是由恶性疟原虫感染的红细胞在微血管中积聚引起的。这一过程由寄生虫的多态红细胞膜蛋白 1（PfEMP1）粘附蛋白介导。通过其CIDRα1结构域与EPCR结合的PfEMP1变体子集，是造成严重疟疾发病的原因。一个长期存在的问题是，单个抗体能否识别循环系统中大量的PfEMP1变体。

研究人员发现了两种对CIDRα1具有广泛反应性和抑制性的人单克隆抗体。从两个不同个体中分离出的抗体，对不同的CIDRα1结构域表现出相似且一致的人内皮蛋白C受体（EPCR）结合抑制作用，代表了CIDRα1六个亚型中的五个。

这两种抗体都抑制了重组全长蛋白和原生PfEMP1蛋白与EPCR的结合，并在生理相关流动条件下的生物工程三维人脑微血管中，抑制了寄生虫的固着。

对这两种抗体与三种不同CIDRα1抗原变体复合物的结构分析表明，它们的结合机制相似，都依赖于EPCR中与CIDRα1结合的三个高度保守的氨基酸残基。

这些具有广泛反应性的抗体，可能代表了获得性免疫重症疟疾的共同机制，并为设计针对重症疟疾的疫苗或治疗方法提供了新的见解。

附：英文原文

Title: Broadly inhibitory antibodies to severe malaria virulence proteins

Author: Reyes, Raphael A., Raghavan, Sai Sundar Rajan, Hurlburt, Nicholas K., Introini, Viola, Bol, Sebastiaan, Kana, Ikhlaq Hussain, Jensen, Rasmus W., Martinez-Scholze, Elizabeth, Gestal-Mato, Mara, Lpez-Gutirrez, Borja, Sanz, Silvia, Bancells, Cristina, Fernndez-Quintero, Monica Lisa, Loeffler, Johannes R., Ferguson, James Alexander, Lee, Wen-Hsin, Martin, Greg Michael, Theander, Thor G., Lusingu, John P. A., Minja, Daniel T. R., Ssewanyana, Isaac, Feeney, Margaret E., Greenhouse, Bryan, Ward, Andrew B., Bernabeu, Maria, Pancera, Marie, Turner, Louise, Bunnik, Evelien M., Lavstsen, Thomas

Issue&Volume: 2024-11-20

Abstract: Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels1. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis2. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.

DOI: 10.1038/s41586-024-08220-3

Source: https://www.nature.com/articles/s41586-024-08220-3