Broadly inhibitory antibodies to severe malaria virulence proteins

• 成果类型: Article
• 署名作者: 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, Maria; Lopez-Gutierrez, Borja; Sanz, Silvia; Bancells, Cristina; Fernandez-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
• 署名单位: University of Texas System; University of Texas at San Antonio; University of Copenhagen; Scripps Research Institute; Fred Hutchinson Cancer Center; National Institute of Medical Research; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5972
• DOI: 10.1038/s41586-024-08220-3
• 发表日期: 2024-12-05
• 关键词: plasmodium-falciparum; infected erythrocytes; acquired-immunity; epcr-binding; cryo-em; surface; pfemp1; antigens; expression; receptor

摘要

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 CIDR alpha 1 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 CIDR alpha 1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDR alpha 1 domains, representing five of the six subclasses of CIDR alpha 1. 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 CIDR alpha 1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDR alpha 1. 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.