Red blood cell blood group A antigen level affects the ability of heparin and PfEMP1 antibodies to disrupt Plasmodium falciparum rosettes

Abstract

Background The histo-blood group ABO system has been associated with adverse outcomes in COVID-19, thromboembolic diseases and Plasmodium falciparum malaria. An integral part of the severe malaria pathogenesis is rosetting, the adherence of parasite infected red blood cells (RBCs) to uninfected RBCs. Rosetting is influenced by the host’s ABO blood group (Bg) and rosettes formed in BgA have previously been shown to be more resilient to disruption by heparin and shield the parasite derived surface antigens from antibodies. However, data on rosetting in weak BgA subgroups is scarce and based on investigations of relatively few donors. Methods An improved high-throughput flow cytometric assay was employed to investigate rosetting characteristics in an extensive panel of RBC donor samples of all four major ABO Bgs, as well as low BgA expressing samples. Results All non-O Bgs shield the parasite surface antigens from strain-specific antibodies towards P. falciparum erythrocyte membrane protein 1 (PfEMP1). A positive correlation between A-antigen levels on RBCs and rosette tightness was observed, protecting the rosettes from heparin- and antibody-mediated disruption. Conclusions These results provide new insights into how the ABO Bg system affects the disease outcome and cautions against interpreting the results from the heterogeneous BgA phenotype as a single group in epidemiological and experimental studies. Graphical Abstract

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

“…Rosetting is probably mediated by both variants of PfEMP1 and RIFINS (repetitive interspersed family proteins), although STEVORs (subtelomeric variable open reading frame proteins) may also be involved [ 62 , 90 ]. Rosetting is enhanced in non-blood group O compared to blood group O erythrocytes [ 62 ], in particular blood group A and AB increase rosette rate and rosette strength [ 91 , 92 ]. Rosettes still form in blood group O suggesting other RBC surface receptors are also involved, and complement receptor 1, glycosaminoglycans (heparan sulphate) and glycophorin C on the surface of uninfected erythrocytes have been implicated [ 62 ].…”

Red Blood Cells Oligosaccharides as Targets for Plasmodium Invasion

“…It was shown that in infected individuals in the A blood group, rosettes are larger, more stable, and occur more frequently than rosettes formed in the O blood group individuals [ 76 , 77 , 78 ]. Moreover, rosettes formed with all non-O blood group RBCs show reduced accessibility for anti-PfEMP1 antibodies [ 79 ]. Thus, it is assumed that rosetting may play a role in the avoiding of immune surveillance and in keeping close ready to infect RBCs [ 80 ].…”

“…Thus, it is assumed that rosetting may play a role in the avoiding of immune surveillance and in keeping close ready to infect RBCs [ 80 ]. A difference in the rosetting of subgroups A 1 and A 2 in RBCs was also found [ 79 , 81 ]. The RBCs of the A 1 subgroup express approximately four to five times more A antigens than those of the A 2 subgroup [ 82 ].…”

“…The RBCs of the A 1 subgroup express approximately four to five times more A antigens than those of the A 2 subgroup [ 82 ]. Therefore, rosettes made with RBCs of A 1 phenotype were larger and less susceptible to anti-PfEMP1 antibodies and the damaging effect of heparin than A 2 -phenotype RBC rosettes [ 79 ]. Moreover, the enzymatic removal of terminal sugars, D-GalNAc and D-Gal, in A and B antigens, respectively, results in smaller, weaker rosettes, similar to those with group O erythrocytes [ 83 , 84 ].…”

Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria

“…The level of A antigen displayed on the RBC surface has been shown to have an impact on rosetting. For example, both rosetting and PfEMP1-binding are substantially reduced in RBCs of the A2 blood group phenotype, in which fewer A antigen sites are displayed per RBC than cells of the common A1 phenotype (16, 17, 39). However, to the best of our knowledge, whether RBCs from AO and BO genotypes differ in their rosette-forming ability compared to RBCs from AA/BB/AB genotypes with higher levels of A and B antigens has not yet been tested.…”