Plasmodium falciparum malaria and carbohydrate blood group evolution C. M. Cserti-Gazdewich Department of Laboratory Hematology, Blood Transfusion Medicine Laboratory & Department of Medicine (Hematology), University Health Network ⁄ Toronto General Hospital, Toronto, Ontario, Canada Plasmodium falciparum malaria, as ancient as hominid evolution itself, has pro- voked more change within the human genome than any other pathogen. JBS Hal- dane observed the overlapping distributions for thalassaemia and malaria endemicity and proposed ‘balanced polymorphisms’ as advantageous heterozygous mutant states. We now appreciate the wider range of haemoglobinopathies, mem- branopathies, and enzymopathies as distinct evolutionary adjustments to the eryth- rocyte, the very compartment which P. falciparum hijacks to sicken the host. Unlike other Plasmodium species, P. falciparum’s power over the erythrocyte con- sists of its limitless red cell infectivity and its capacity to render the infected red blood cell (iRBC) adhesive enough to arrest in the circulation. This latter cytoadhe- sivity is achieved by sticky knob proteins known as ‘Plasmodium falciparum eryth- rocyte membrane protein-1’ (PfEMP-1), trafficked to the red cell exterior from the parasite within. PfEMP-1 is designed to latch onto endothelial cells of the post-cap- illary venules (‘sequestration’), as well as onto other uninfected red blood cells and platelets (‘rosetting’). In so stalling their flow towards the spleen, the iRBC doubly harms the host by resisting the first defence of reticuloendothelial clearance and congesting the host’s microvasculature. The youngest, most malaria-naı ¨ve suffer malaria’s highest case fatality rates, revealing just how critical this innate (pre- adaptive) immune control of parasitaemia is. The biochemical means by which PfEMP-1 achieves its cytoadhesive promiscuity is in part through one particular lectin-like domain, DBL1a. This domain binds not only to heparan sulphate-like glycosaminoglycans, but to two blood group antigens expressed densely on ery- throcytes: the group A carbohydrate in the ABO system and antigens (including those of the Knops system) on CR1 (CD35). If indeed these ligands are critical in the molecular pathogenesis of malaria fatalities, then we might expect to observe non- adhesive variants ascending to higher prevalence in the most malaria-endemic parts of the world. The cytoadhesivity of wildtype group A hosts is theoretically, and in vitro, demonstrably mitigated by what we now know are the mutant pheno- types which define the polymorphisms of the ABO system. These include the group O or B alleles, the weaker A types and the genetics influencing the quantity of secreted (competitive) free A antigen in group A hosts. Each of these phenotypes is observed at higher frequencies in malaria-endemic areas. Certain CR1 polymor- phisms are also more frequently found in these parts of the world. The assembly of in vitro, geographic and clinical evidence weighs heavily towards ABO evolution being a highly specific response to P. falciparum. Rather than bypassing invasion or enhancing clearance, these mutations are special because they highlight the Correspondence: Christine M Cserti-Gazdewich, University Health Network ⁄ Toronto General Hospital, Department of Laboratory Hematology, Blood Transfusion Medicine Laboratory, Department of Medicine, Hematology, 3EC-306, 200 Elizabeth Street, Toronto, Ontario M5G-2C4, Canada E-mail: Christine.Cserti@uhn.on.ca ISBT Science Series (2010) 5, 256–266 STATE OF THE ART 5C-S40-02 ª 2010 The Author. Journal compilation ª 2010 International Society of Blood Transfusion 256