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Structure paper

TitleBroadly inhibitory antibodies to severe malaria virulence proteins.
Journal, issue, pagesNature, Vol. 636, Issue 8041, Page 182-189, Year 2024
Publish dateNov 20, 2024
AuthorsRaphael A Reyes / Sai Sundar Rajan Raghavan / Nicholas K Hurlburt / Viola Introini / Sebastiaan Bol / Ikhlaq Hussain Kana / Rasmus W Jensen / Elizabeth Martinez-Scholze / María Gestal-Mato / Borja López-Gutiérrez / Silvia Sanz / Cristina Bancells / Monica Lisa Fernández-Quintero / Johannes R Loeffler / James Alexander Ferguson / Wen-Hsin Lee / Greg Michael Martin / Thor G Theander / John P A Lusingu / Daniel T R Minja / Isaac Ssewanyana / Margaret E Feeney / Bryan Greenhouse / Andrew B Ward / Maria Bernabeu / Marie Pancera / Louise Turner / Evelien M Bunnik / Thomas Lavstsen /
PubMed AbstractMalaria 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) ...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.
External linksNature / PubMed:39567685 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.68 - 5.0 Å
Structure data

43148

8vdf

EMDB-43148, PDB-8vdf:
Cryo-EM structure of human monoclonal antibody C7 targeting IT4VAR22 CIDRa1.7 (PfEMP1 A)
Method: EM (single particle) / Resolution: 3.5 Å

43149

8vdg

EMDB-43149, PDB-8vdg:
Cryo-EM structure of human monoclonal antibody C74 targeting IT4VAR22 CIDRa1.7
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-43150: Human monoclonal antibody C7 targeting HB3VAR03 (PfEMP1 A)
Method: EM (single particle) / Resolution: 5.0 Å

44539

9bhb

EMDB-44539, PDB-9bhb:
Cryo-EM structure of human monoclonal antibody C74 targeting PFD1235w (CIDRa1.6) PfEMP1
Method: EM (single particle) / Resolution: 3.1 Å

PDB-8vdl:
HB3VAR03 CIDRa1.4 domain with C7 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.68 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • plasmodium falciparum (malaria parasite P. falciparum)
  • plasmodium falciparum 3d7 (eukaryote)
  • plasmodium falciparum hb3 (eukaryote)
KeywordsIMMUNE SYSTEM / Malaria / PfEMP1 / Human monoclonal antibodies / Severe malaria. / Plasmodium falciparum / Antibody / Plasmodium / Monoclonal / Neutralizing

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