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 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.
Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France.
Inès
I
Vigan-Womas
Micheline
M
Guillotte
Alexandre
A
Juillerat
Audrey
A
Hessel
Bertrand
B
Raynal
Patrick
P
England
Jacques H
JH
Cohen
Olivier
O
Bertrand
Thierry
T
Peyrard
Graham A
GA
Bentley
Anita
A
Lewit-Bentley
Odile
O
Mercereau-Puijalon
D000017:ABO Blood-Group System / Q000276:immunology / Q000378:metabolism*; D000595:Amino Acid Sequence; D000913:Antibodies, Protozoan / Q000276:immunology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007104:Immune Adherence Reaction; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology / Q000469:parasitology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012397:Rosette Formation
D000017:ABO Blood-Group System; D000913:Antibodies, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum