<b>Malaria tropica in blood group A compensates for </b><b><i>Plasmodium falciparum's</i></b><b> inability to synthezise the amino sugar N-acetyl-D-galactosamine (GalNAc)</b>

The protozoan parasite <i>Plasmodium falciparum</i>, the pathogen of malaria tropica, does not execute the evolutionary, developmental first (glyco)protein glycosylation or the blood group-independent, serologically A-like, <i>O</i>-GalNAcα1-Ser/Thr-R, Tn antigen ("T nouvelle") formation of the metazoan host, due to its inability to synthesise the amino sugar N-acetyl-D-galactosamine (GalNAc). The broad biological and evolutionary implications of this genetic disorder, which causes life-threatening malaria tropica, a major global public health problem and one of the world's deadliest diseases, in our analysis reveals a previously unknown molecular mechanism of infection that is not limited to malaria. Species co-evolution drives diversity in animals and plants, whereas parasites that lack essential life functions compensate by exploiting the host cell machinery. In malaria tropica, the parasite <i>Plasmodium falciparum</i> does not encode the biologically indispensable aminosugar GalNAc (N-acetyl-D-galactosamine), and its abundantly expressed serine molecule becomes linked to host GalNAc, catalysed by the blood group-independent polypeptide GalNAc transferase, which initiates infection. The resulting hybrid <i>O</i>-GalNAcα1-Ser/Thr-R, mucin type A-like/Tn ("T nouvelle") antigen represents the first step in pathogenesis, which in blood group A is completed by specific glycosylation, encoded by the A allele, neutralising the pre-existing anti-A-like/Tn reactivity of poly-reactive IgM and precluding A-phenotypic autoimmunity. In blood group O(H), this antibody blocks the formation of a hybrid A-like/Tn antigen, whereas in blood group A individuals, the duplication of host-pathogen exposure by two genetically distinct bindings and the neutralisation of anti-A-like/Tn IgM reactivity explain the increased susceptibility and severity of disease in this group.<br>