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

2017

Article référencé dans le Web of Science WOS:000396375600025

Lennartz F., Adams Y., Bengtsson A., Olsen R. W., Turner L., Tuikue Ndam Nicaise, Ecklu-Mensah G., Moussiliou A., Ofori M. F., Gamain B., Lusingu J. P., Petersen J. E. V., Wang C. W., Nunes-Silva S., Jespersen J. S., Lau C. K. Y., Theander T. G., Lavstsen T., Hviid L., Higgins M. K., Jensen A. T. R.

Cell Host and Microbe, 2017, 21 (3), p. 403-414 ISSN 1931-3128

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.

Santé : généralités [050] ; Entomologie médicale / Parasitologie / Virologie [052]

Fonds IRD [F B010069279]

fdi:010069279