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

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 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.

ABO blood group distribution among endemic Burkitt’s lymphoma patients in Nigeria: Further evidence for the aetiological role of malaria

“…These changes were associated with significant Odds ratios suggesting decreased and increased risks of eBL among individuals with O and non-O blood groups respectively. These findings are interpreted to be a reflection of decreased and increased risks of severe malaria in individuals with O and non-O blood groups respectively as previously reported in earlier studies [3,4,12,13]. Previous studies have shown that malaria was associated with immune suppression, increased EBV load and polyclonal B cell activation, all of which are important in the pathogenesis of eBL [1,7].…”

“…Previous studies have shown that malaria was associated with immune suppression, increased EBV load and polyclonal B cell activation, all of which are important in the pathogenesis of eBL [1,7]. These malaria induced immune deregulations would be greater in persons with non-O blood groups because of their vulnerability to severe malaria [3,4,12,13]. Conversely, persons with O blood group, which is associated with non-severe malaria, would incur milder malaria associated pathology because of their reduced vulnerability to severe malaria [3,4,12,14].…”

Glycophorin C (CD236R) mediates vivax malaria parasite rosetting to normocytes

“…This is because one of the ligands associated with rosette formation in P falciparum (P falciparum erythrocyte membrane protein 1 [PfEMP1]) has no orthologs in P vivax. Thus, all of the receptors on the host red cell corresponding to PfEMP1, such as complement receptor 1 (CD35), 27 blood group antigens (A and B), [28][29][30] heparan sulfate, 31 and thrombospondin (CD36), 32,33 may not be relevant to P vivax rosette formation.…”

Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

“…In contrast, in the structure of the N‐terminal DBL1‐CIDR1 didomain of var0, the CIDR domain forms a compact α‐helical bundle. This packs tightly against the DBL domain through an additional region containing a four‐stranded anti‐parallel β‐sheet 41. Whether different CIDR domains adopt different architectures, or whether truncation of the MC179 CIDR domain or the crystallization conditions have caused this structure to spread apart, remains to be seen and will require the determination of more CIDR structures, alone and in complex with their ligands.…”