Broadly inhibitory antibodies to severe malaria virulence proteins

Affiliations

• Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
• Centre for Translational Medicine and Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark
• Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
• Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
• EMBL Barcelona, Barcelona, Spain
• National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania
• Infectious Disease Research Collaboration, Kampala, Uganda
• Department of Medicine, University of California San Francisco, San Francisco, CA, USA
• Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

PMID:    DOI: 10.1038/s41586-024-08220-3

Abstract

Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels. 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 pathogenesis. 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.

疟疾的病理由疟原虫恶性疟（Plasmodium falciparum）感染的红细胞在微血管中的积累所驱动。这一过程由寄生虫的多态性红细胞膜蛋白1（PfEMP1）粘附蛋白介导。通过其CIDRα1结构域与人类内皮蛋白C受体（EPCR）结合的PfEMP1变体亚群负责严重疟疾的发病机制。一个长期存在的问题是，个体抗体是否能够识别大量循环的PfEMP1变体。本文描述了两种对CIDRα1具有广泛反应性和抑制性的人的单克隆抗体。这些抗体来自两位不同的个体，展示了对多种CIDRα1结构域的一致性EPCR结合抑制作用，代表了CIDRα1六个亚类中的五个。两种抗体均能抑制重组全长PfEMP1蛋白和天然PfEMP1蛋白与EPCR的结合，并在生物工程化的3D人脑微血管中，在生理相关流动条件下抑制寄生虫的隔离。对这两种抗体与三种不同CIDRα1抗原变体复合物的结构分析揭示了相似的结合机制，依赖于与CIDRα1中EPCR结合位点三个高度保守氨基酸残基的相互作用。这些广泛反应性抗体可能代表了对严重疟疾获得性免疫的共同机制，并为设计针对严重疟疾的疫苗或治疗提供了新的见解。

关键词：疟疾，疟原虫，PfEMP1，EPCR，CIDRa，C7，C74，中和抗体，广谱中和抗体，中和抗体试剂盒，佰乐博，佰乐博生物