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

Frank Lennartz; Yvonne Adams; Anja Bengtsson; Rebecca W Olsen; Louise Turner; Nicaise T Ndam; Gertrude Ecklu-Mensah; Azizath Moussiliou; Michael F Ofori; Benoit Gamain; John P Lusingu; Jens E V Petersen; Christian W Wang; Sofia Nunes-Silva; Jakob S Jespersen; Clinton K Y Lau; Thor G Theander; Thomas Lavstsen; Lars Hviid; Matthew K Higgins; Anja T R 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 W Olsen, Louise Turner, Nicaise T Ndam, Gertrude Ecklu-Mensah, Azizath Moussiliou, Michael F Ofori, Benoit Gamain, John P Lusingu, Jens E V Petersen, Christian W Wang, Sofia Nunes-Silva, Jakob S Jespersen, Clinton K Y Lau, Thor G Theander, Thomas Lavstsen, Lars Hviid, Matthew K HigginsAnja T R Jensen

156 Citations (Scopus)

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 and 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

Keywords

Antigens, CD
Cell Adhesion
Computational Biology
Crystallography, X-Ray
Endothelial Protein C Receptor
Genome, Protozoan
Intercellular Adhesion Molecule-1
Malaria, Cerebral
Malaria, Falciparum
Plasmodium falciparum
Protein Binding
Protozoan Proteins
Receptors, Cell Surface
Scattering, Small Angle
Sequence Analysis, DNA
Surface Plasmon Resonance
Virulence Factors
Journal Article

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Lennartz, F., Adams, Y., Bengtsson, A., Olsen, R. W., Turner, L., Ndam, N. T., 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., ... Jensen, A. T. R. (2017). Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria. Cell Host and 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, G, 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 and 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.",

keywords = "Antigens, CD, Cell Adhesion, Computational Biology, Crystallography, X-Ray, Endothelial Protein C Receptor, Genome, Protozoan, Intercellular Adhesion Molecule-1, Malaria, Cerebral, Malaria, Falciparum, Plasmodium falciparum, Protein Binding, Protozoan Proteins, Receptors, Cell Surface, Scattering, Small Angle, Sequence Analysis, DNA, Surface Plasmon Resonance, Virulence Factors, Journal Article",

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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 W

AU - Turner, Louise

AU - Ndam, Nicaise T

AU - Ecklu-Mensah, Gertrude

AU - Moussiliou, Azizath

AU - Ofori, Michael F

AU - Gamain, Benoit

AU - Lusingu, John P

AU - Petersen, Jens E V

AU - Wang, Christian W

AU - Nunes-Silva, Sofia

AU - Jespersen, Jakob S

AU - Lau, Clinton K Y

AU - Theander, Thor G

AU - Lavstsen, Thomas

AU - Hviid, Lars

AU - Higgins, Matthew K

AU - Jensen, Anja T R

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.

KW - Antigens, CD

KW - Cell Adhesion

KW - Computational Biology

KW - Crystallography, X-Ray

KW - Endothelial Protein C Receptor

KW - Genome, Protozoan

KW - Intercellular Adhesion Molecule-1

KW - Malaria, Cerebral

KW - Malaria, Falciparum

KW - Plasmodium falciparum

KW - Protein Binding

KW - Protozoan Proteins

KW - Receptors, Cell Surface

KW - Scattering, Small Angle

KW - Sequence Analysis, DNA

KW - Surface Plasmon Resonance

KW - Virulence Factors

KW - Journal Article

UR - https://www.scopus.com/pages/publications/85014755683

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 -

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

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Keywords

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