Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria

TY - JOUR

T1 - Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria

AU - Lennartz, Frank

AU - Adams, Yvonne

AU - Bengtsson, Anja

AU - Olsen, Rebecca Wendelboe

AU - Turner, Louise

AU - Ndam, Nicaise T

AU - Ecklu-Mensah, Gertrude Delali

AU - Moussiliou, Azizath

AU - Ofori, Michael F

AU - Gamain, Benoit

AU - Lusingu, John P.

AU - Petersen, Jens Emil Vang

AU - Wang, Christian William

AU - Nunes-Silva, Sofia

AU - Jespersen, Jakob Schmidt

AU - Lau, Clinton K Y

AU - Theander, Thor Grundtvig

AU - Lavstsen, Thomas

AU - Hviid, Lars

AU - Higgins, Matthew K

AU - Jensen, Anja Tatiana Ramstedt

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2017/3/8

Y1 - 2017/3/8

N2 - 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.

AB - 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.

U2 - 10.1016/j.chom.2017.02.009

DO - 10.1016/j.chom.2017.02.009

M3 - Journal article

C2 - 28279348

SN - 1931-3128

VL - 21

SP - 403

EP - 414

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 3

ER -