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Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria

DOI: 10.1016/j.chom.2017.02.009 DOI Help

Authors: Frank Lennartz (University of Oxford) , Yvonne Adams (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Anja Bengtsson (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Rebecca W. Olsen (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Louise Turner (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Nicaise T. Ndam (COMUE Sorbonne Paris Cité) , Gertrude Ecklu-mensah (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet); University of Ghana) , Azizath Moussiliou (Université d’Aboméy Calavi) , Michael F. Ofori (University of Ghana) , Benoit Gamain (Université Sorbonne Paris Cité) , John P. Lusingu (National Institute for Medical Research, Tanzania) , Jens E. V. Petersen (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Christian W. Wang (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Sofia Nunes-silva (Université Sorbonne Paris Cité) , Jakob S. Jespersen (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Clinton K. Y. Lau (University of Oxford) , Thor G. Theander (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Thomas Lavstsen (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Lars Hviid (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet)) , Matthew K. Higgins (University of Oxford) , Anja T. R. Jensen (University of Copenhagen; Copenhagen University Hospital (Rigshospitalet))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Host & Microbe , VOL 21 , PAGES 403 - 414

State: Published (Approved)
Published: March 2017

Open Access Open Access

Abstract: Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.

Journal Keywords: cerebral malaria; Plasmodium falciparum; ICAM-1; EPCR; PfEMP1

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Documents:
1-s2.0-S1931312817300719-main.pdf

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