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A Simple Protocol for Platelet-mediated Clumping of Plasmodium falciparum-infected Erythrocytes in a Resource Poor Setting
Published on: May 16, 2013
Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting
Inès Vigan-Womas1, Micheline Guillotte, Alexandre Juillerat
1Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France.
Abstract:
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.
Insights
The ABO blood group dictates Plasmodium falciparum malaria severity by influencing infected red blood cell rosetting. Group O offers protection, while specific ABO blood groups bind differently to the malaria parasite
Area of Science:
- Malariology
- Immunogenetics
- Structural Biology
Background:
- The ABO blood group system significantly impacts susceptibility to severe Plasmodium falciparum malaria.
- Group O is associated with reduced rosetting of infected red blood cells (iRBCs) by uninfected RBCs, a key mechanism in malaria pathogenesis.
- Rosetting is mediated by specific Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) adhesins, particularly their N-terminal DBL1α₁ domain.
Purpose of the Study:
- To identify the ABO blood group receptor for the VarO PfEMP1 adhesin mediating iRBC rosetting.
- To elucidate the structural basis of ABO blood group preference in VarO-mediated rosetting.
- To explore potential therapeutic targets for severe malaria based on conserved binding mechanisms.
Main Methods:
- Recombinant protein expression (NTS-DBL1α₁-CIDR1γ) to mimic VarO adhesin function.
- Surface plasmon resonance to quantify binding to blood group trisaccharides.
- X-ray crystallography to determine the high-resolution structure of the PfEMP1-VarO head region.
- Computer-aided molecular docking and site-directed mutagenesis to map the RBC binding site.
Main Results:
- The ABO blood group is the primary receptor for VarO-mediated rosetting, with a preference order of A > B > O.
- Direct binding of the VarO adhesin to blood group trisaccharides was confirmed, with specific affinities for subgroups A₁, A₂, B, A(x), and O.
- The crystal structure revealed essential contacts and identified the NTS-DBL1α₁ hinge region as critical for RBC binding.
- The RBC binding site was localized to a specific face of the DBL1α₁ domain, distinct from the heparin-binding site.
Conclusions:
- Deciphered the structural basis for ABO blood group preference in Plasmodium falciparum rosetting.
- Established a direct link between ABO blood group polymorphisms and the binding properties of rosette-forming PfEMP1 adhesins.
- Identified conserved residues involved in RBC binding, presenting novel targets for anti-malarial interventions.
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