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Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting

The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhes...

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Autores principales: Vigan-Womas, Inès, Guillotte, Micheline, Juillerat, Alexandre, Hessel, Audrey, Raynal, Bertrand, England, Patrick, Cohen, Jacques H., Bertrand, Olivier, Peyrard, Thierry, Bentley, Graham A., Lewit-Bentley, Anita, Mercereau-Puijalon, Odile
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395597/
https://www.ncbi.nlm.nih.gov/pubmed/22807674
http://dx.doi.org/10.1371/journal.ppat.1002781
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author Vigan-Womas, Inès
Guillotte, Micheline
Juillerat, Alexandre
Hessel, Audrey
Raynal, Bertrand
England, Patrick
Cohen, Jacques H.
Bertrand, Olivier
Peyrard, Thierry
Bentley, Graham A.
Lewit-Bentley, Anita
Mercereau-Puijalon, Odile
author_facet Vigan-Womas, Inès
Guillotte, Micheline
Juillerat, Alexandre
Hessel, Audrey
Raynal, Bertrand
England, Patrick
Cohen, Jacques H.
Bertrand, Olivier
Peyrard, Thierry
Bentley, Graham A.
Lewit-Bentley, Anita
Mercereau-Puijalon, Odile
author_sort Vigan-Womas, Inès
collection PubMed
description The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α(1) domain. Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs. We show that recombinant NTS-DBL1α(1) and NTS-DBL1α(1)-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance. More detailed RBC subgroup analysis showed preferred binding to group A(1), weaker binding to groups A(2) and B, and least binding to groups A(x) and O. The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α(1)-CIDR1γ, reveals extensive contacts between the DBL1α(1) and CIDR1γ and shows that the NTS-DBL1α(1) hinge region is essential for RBC binding. Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα(1). RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria. By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup.
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spelling pubmed-33955972012-07-17 Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting Vigan-Womas, Inès Guillotte, Micheline Juillerat, Alexandre Hessel, Audrey Raynal, Bertrand England, Patrick Cohen, Jacques H. Bertrand, Olivier Peyrard, Thierry Bentley, Graham A. Lewit-Bentley, Anita Mercereau-Puijalon, Odile PLoS Pathog Research Article The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α(1) domain. Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs. We show that recombinant NTS-DBL1α(1) and NTS-DBL1α(1)-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance. More detailed RBC subgroup analysis showed preferred binding to group A(1), weaker binding to groups A(2) and B, and least binding to groups A(x) and O. The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α(1)-CIDR1γ, reveals extensive contacts between the DBL1α(1) and CIDR1γ and shows that the NTS-DBL1α(1) hinge region is essential for RBC binding. Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα(1). RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria. By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup. Public Library of Science 2012-07-12 /pmc/articles/PMC3395597/ /pubmed/22807674 http://dx.doi.org/10.1371/journal.ppat.1002781 Text en Vigan-Womas et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vigan-Womas, Inès
Guillotte, Micheline
Juillerat, Alexandre
Hessel, Audrey
Raynal, Bertrand
England, Patrick
Cohen, Jacques H.
Bertrand, Olivier
Peyrard, Thierry
Bentley, Graham A.
Lewit-Bentley, Anita
Mercereau-Puijalon, Odile
Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting
title Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting
title_full Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting
title_fullStr Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting
title_full_unstemmed Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting
title_short Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting
title_sort structural basis for the abo blood-group dependence of plasmodium falciparum rosetting
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395597/
https://www.ncbi.nlm.nih.gov/pubmed/22807674
http://dx.doi.org/10.1371/journal.ppat.1002781
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