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
VL - 21
SP - 403
EP - 414
JO - Cell Host & Microbe
JF - Cell Host & Microbe
SN - 1931-3128
IS - 3
ER -