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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2012
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oai:doaj.org-article:d0409c6651fb4a2d9ca02f49988aadf02021-11-18T06:04:13ZStructural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting.1553-73661553-737410.1371/journal.ppat.1002781https://doaj.org/article/d0409c6651fb4a2d9ca02f49988aadf02012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22807674/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The 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 DBL1α₁ 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-DBL1α₁ and NTS-DBL1α₁-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 A₁, weaker binding to groups A₂ 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-DBL1α₁-CIDR1γ, reveals extensive contacts between the DBL1α₁ and CIDR1γ and shows that the NTS-DBL1α₁ 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-DBLα₁. 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.Inès Vigan-WomasMicheline GuillotteAlexandre JuilleratAudrey HesselBertrand RaynalPatrick EnglandJacques H CohenOlivier BertrandThierry PeyrardGraham A BentleyAnita Lewit-BentleyOdile Mercereau-PuijalonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 7, p e1002781 (2012) |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Inès Vigan-Womas Micheline Guillotte Alexandre Juillerat Audrey Hessel Bertrand Raynal Patrick England Jacques H Cohen Olivier Bertrand Thierry Peyrard Graham A Bentley Anita Lewit-Bentley Odile Mercereau-Puijalon Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting. |
| 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 DBL1α₁ 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-DBL1α₁ and NTS-DBL1α₁-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 A₁, weaker binding to groups A₂ 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-DBL1α₁-CIDR1γ, reveals extensive contacts between the DBL1α₁ and CIDR1γ and shows that the NTS-DBL1α₁ 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-DBLα₁. 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. |
| format |
article |
| author |
Inès Vigan-Womas Micheline Guillotte Alexandre Juillerat Audrey Hessel Bertrand Raynal Patrick England Jacques H Cohen Olivier Bertrand Thierry Peyrard Graham A Bentley Anita Lewit-Bentley Odile Mercereau-Puijalon |
| author_facet |
Inès Vigan-Womas Micheline Guillotte Alexandre Juillerat Audrey Hessel Bertrand Raynal Patrick England Jacques H Cohen Olivier Bertrand Thierry Peyrard Graham A Bentley Anita Lewit-Bentley Odile Mercereau-Puijalon |
| author_sort |
Inès Vigan-Womas |
| title |
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_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_sort |
structural basis for the abo blood-group dependence of plasmodium falciparum rosetting. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/d0409c6651fb4a2d9ca02f49988aadf0 |
| work_keys_str_mv |
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