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

Frank Lennartz; Yvonne Adams; Anja Bengtsson; Rebecca Wendelboe Olsen; Louise Turner; Nicaise T Ndam; Gertrude Delali Ecklu-Mensah; Azizath Moussiliou; Michael F Ofori; Benoit Gamain; John P. Lusingu; Jens Emil Vang Petersen; Christian William Wang; Sofia Nunes-Silva; Jakob Schmidt Jespersen; Clinton K Y Lau; Thor Grundtvig Theander; Thomas Lavstsen; Lars Hviid; Matthew K Higgins; Anja Tatiana Ramstedt Jensen

doi:10.1016/j.chom.2017.02.009

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

Frank Lennartz, Yvonne Adams, Anja Bengtsson, Rebecca Wendelboe Olsen, Louise Turner, Nicaise T Ndam, Gertrude Delali Ecklu-Mensah, Azizath Moussiliou, Michael F Ofori, Benoit Gamain, John P. Lusingu, Jens Emil Vang Petersen, Christian William Wang, Sofia Nunes-Silva, Jakob Schmidt Jespersen, Clinton K Y Lau, Thor Grundtvig Theander, Thomas Lavstsen, Lars Hviid, Matthew K HigginsAnja Tatiana Ramstedt Jensen

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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.

Original language	English
Journal	Cell Host & Microbe
Volume	21
Issue number	3
Pages (from-to)	403-414
Number of pages	12
ISSN	1931-3128
DOIs	https://doi.org/10.1016/j.chom.2017.02.009
Publication status	Published - 8 Mar 2017

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Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malariaFinal published version, 4.07 MBLicence: CC BY

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Lennartz, F., Adams, Y., Bengtsson, A., Olsen, R. W., Turner, L., Ndam, N. T., Ecklu-Mensah, G. D., 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., ... Jensen, A. T. R. (2017). Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria. Cell Host & Microbe, 21(3), 403-414. https://doi.org/10.1016/j.chom.2017.02.009

Lennartz, F, Adams, Y , Bengtsson, A , Olsen, RW , Turner, L, Ndam, NT, Ecklu-Mensah, GD, Moussiliou, A, Ofori, MF, Gamain, B, Lusingu, JP, Petersen, JEV , Wang, CW, Nunes-Silva, S, Jespersen, JS, Lau, CKY, Theander, TG , Lavstsen, T , Hviid, L, Higgins, MK & Jensen, ATR 2017, 'Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria', Cell Host & Microbe, vol. 21, no. 3, pp. 403-414. https://doi.org/10.1016/j.chom.2017.02.009

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

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.",

author = "Frank Lennartz and Yvonne Adams and Anja Bengtsson and Olsen, {Rebecca Wendelboe} and Louise Turner and Ndam, {Nicaise T} and Ecklu-Mensah, {Gertrude Delali} and Azizath Moussiliou and Ofori, {Michael F} and Benoit Gamain and Lusingu, {John P.} and Petersen, {Jens Emil Vang} and Wang, {Christian William} and Sofia Nunes-Silva and Jespersen, {Jakob Schmidt} and Lau, {Clinton K Y} and Theander, {Thor Grundtvig} and Thomas Lavstsen and Lars Hviid and Higgins, {Matthew K} and Jensen, {Anja Tatiana Ramstedt}",

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doi = "10.1016/j.chom.2017.02.009",

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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

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 & Microbe

JF - Cell Host & Microbe

IS - 3

ER -

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

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