Malaria tropica evades host immunity through ABO blood group hybridization

The coevolution of species drives diversity in animals and plants and contributes to natural selection, while in host–parasite coevolution, a parasite may complete an incomplete evolutionary/developmental function by utilizing the host cell’s machinery. Analysis of related older data suggests that Plasmodium falciparum (P. falciparum), the pathogen of malaria tropica, cannot survive outside its human host because it is unable to perform the evolutionarily first protein glycosylation or blood group-independent (serologically A-like) O-GalNAcα1-Ser/Thr-R, Tn antigen (“T nouvelle”) formation owing to its inability for synthesizing the amino sugar N-acetyl-d-galactosamine (GalNAc). This parasite breaks the species barrier via hijacking the host's A-like/Tn formation by abundantly expressing serine residues and creating hybrid A-like/Tn structures. In the human blood group O(H), these hybrid structures are attacked by the germline-encoded nonimmune polyreactive immunoglobulin M (IgM), which physiologically regulates the expression of the syngeneic A-like/Tn antigen. In non-O blood groups, this antibody molecule has undergone the phenotypic accommodation of plasma proteins, which results in loss of blood group A- and B-corresponding anti-A and anti-B isoagglutinin activities. This loss allows the generation of human A- and B allele-connected hybrid epitopes and the development of life-threatening disease almost exclusively in non-O blood groups. Although malaria infection occurs regardless of the blood group, the synthesis of the blood group AB enables the strongest contact with the pathogen, and molecularly precluding any isoagglutinin activity makes this group the least protected and the smallest among the ABO blood groups. In contrast, blood group O(H) individuals have the least contact with the pathogen; they maintain the isoagglutinins, rarely develop severe disease, and survive this coevolution in an immunological balance with the pathogen as the largest blood group worldwide.