Broadly inhibitory antibodies against severe malaria virulence proteins.

Autor:	Reyes RA; Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Raghavan SSR; Centre for translational Medicine & 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 92037, USA., Hurlburt NK; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Introini V; European Molecular Biology Laboratory (EMBL) Barcelona, Barcelona 08003, Spain., Kana IH; Centre for translational Medicine & Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark., Jensen RW; Centre for translational Medicine & Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark., Martinez-Scholze E; Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Gestal-Mato M; European Molecular Biology Laboratory (EMBL) Barcelona, Barcelona 08003, Spain., Bau CB; European Molecular Biology Laboratory (EMBL) Barcelona, Barcelona 08003, Spain., Fernández-Quintero ML; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Loeffler JR; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Ferguson JA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Lee WH; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Martin GM; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Theander TG; Centre for translational Medicine & Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark., Ssewanyana I; Infectious Disease Research Collaboration, Kampala, Uganda., Feeney ME; Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94110, USA., Greenhouse B; Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA., Bol S; Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Ward AB; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Bernabeu M; European Molecular Biology Laboratory (EMBL) Barcelona, Barcelona 08003, Spain., Pancera M; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Turner L; Centre for translational Medicine & Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark., Bunnik EM; Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Lavstsen T; Centre for translational Medicine & Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Righospitalet, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 25. Date of Electronic Publication: 2024 Jan 25.
DOI:	10.1101/2024.01.25.577124
Abstrakt:	Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process is mediated by the parasite's polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset of PfEMP1 variants that bind 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 binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies isolated from two different individuals exhibited a similar and consistent EPCR-binding inhibition of 34 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 brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with two 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 likely 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. Competing Interests: Declaration of Interests The Authors declare no competing interests.
Databáze:	MEDLINE
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