• ABO;
  • blood group;
  • CD35;
  • CR1;
  • evolution;
  • Knops;
  • Lewis;
  • malaria;
  • Plasmodium falciparum;
  • secretor


  1. Top of page
  2. Abstract
  3. ‘Arms-race’ evolution between malaria and man
  4. Plasmodium falciparum as the most malignant of the malarias
  5. The ABO blood group system and P. falciparum malaria: evidence for selection pressures against Group A antigens, rather than for the mutant O isohaemagglutinins
  6. Acknowledgements
  7. Disclosures
  8. References

Plasmodium falciparum malaria, as ancient as hominid evolution itself, has provoked more change within the human genome than any other pathogen. JBS Haldane 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, membranopathies, and enzymopathies as distinct evolutionary adjustments to the erythrocyte, the very compartment which P. falciparum hijacks to sicken the host. Unlike other Plasmodium species, P. falciparum’s power over the erythrocyte consists 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 cytoadhesivity is achieved by sticky knob proteins known as ‘Plasmodium falciparum erythrocyte 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-capillary 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-naïve 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, DBL1α. This domain binds not only to heparan sulphate-like glycosaminoglycans, but to two blood group antigens expressed densely on erythrocytes: 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 phenotypes 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 polymorphisms 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 importance of escape from cytoadhesion. Forthcoming are the results of the first prospective study powered to confirm the impact of ABO on malaria mortality (NCT 00707200, Should the results of emerging studies confirm a survival advantage among group O individuals, the basic strategy for transfusion support in malaria may shift to greater use of group O red cells. The clinical value of this approach, more immediately available than any new drug or vaccine development, will need to be tested in clinical trials.

‘Arms-race’ evolution between malaria and man

  1. Top of page
  2. Abstract
  3. ‘Arms-race’ evolution between malaria and man
  4. Plasmodium falciparum as the most malignant of the malarias
  5. The ABO blood group system and P. falciparum malaria: evidence for selection pressures against Group A antigens, rather than for the mutant O isohaemagglutinins
  6. Acknowledgements
  7. Disclosures
  8. References

Plasmodium and human co-evolution

For as long as the malaria-causing Plasmodium genus has existed, the phylogenetic diversification of its terrestrial hosts has never managed to achieve a sustained and unchallenged escape. Plasmodium falciparum malaria, of greatest concern to humanity, has in turn provoked more discernable change within our genome [1] than any other pathogen we have ever known. Human and P. falciparum co-evolution is a story of nearly immediate retaliatory genetics over time, now well documented in the historical sciences [2] and even modern blood group immunohaematology.

The coexistence of Plasmodia and Class Mammalia dates back to the origins of each 200 million years ago. Multiple species of Plasmodium were ready for primates as soon as they arrived, and according to the co-speciation hypothesis, the most malignant species which affect humans and chimpanzees, P. falciparum and P. reichenowi, respectively, sprang up in perfect parallel with the hominid divergence [3,4]. The group O mutation occurred roughly 5 million years ago [5], predating the emergence of H. sapiens 200 000 years ago [6,7] in malaria-endemic Africa. Emigrations out of the mother continent began some 50 000 years later, with the global dispersion of humans not completed until 10 000 years ago [8]. The exodus funnelled a narrower base of genetic diversity out Africa, reflecting the balance of adaptive mutations achieved by that time, including the earlier O:A ratios. Colonization of all parts of the new world, with concomitantly or subsequently re-imported malaria, then incubated differential endemicities, depending upon the climate and man-made environmental changes. The selection pressure of malaria has never been as intense since the advent of agriculture [9], when the increasing abundance of human life tempted the parasite’s increasing ‘anthropophily’. Riverine man’s dominion over flora and fauna may have encroached too deeply upon chimpanzees when modern-day P. falciparum re-diverged (or de-novo originated) from P. reichenowi [10–12]. The global unleashing of this next most virulent form of P. falciparum has suggested a more recent origin [13], with demographic or selective sweep (Darwinian take-over) by this eclipsing latter-day malarial Eve. With the recent discovery of another form of HIV resulting from a re-crossing of an alternative species barrier [14], it is not inconceivable that multiple models for the evolution of P. falciparum from P. reichenowi may likewise be tenable.

The rampaging force of modern P. falciparum appears to account for the tremendous heterogeneity of, and the unusually rapid rise of, reciprocal human adaptations in the far reaches of its hold. Darwinian accounting encourages the rise of a sporadic malaria-mitigating mutant allele in those parts of the world where malaria is both common and lethal, as long as the still-significant price of disease from mutant homozygosity is less than the malaria itself. JBS Haldane first observed the overlapping distributions for thalassaemia and malaria endemicity and proposed ‘balanced polymorphisms’ [15] as genomic makeovers capped by the conditions of nature’s highest net gains.

A number of malaria-specific balanced red cell polymorphisms (e.g. structural and quantitative haemoglobinopathies [16,17], cytoskeleton-membranopathies [18,19], enzymopathies [20,21]) and blood group antigen polymorphisms (ABO, Duffy, MNS, Knops) [22] have thus arisen independently throughout sub-Saharan Africa, the Mediterranean and South East Asia. During the same period, the distribution of ABO types continued to shift under regional malarial pressure and other more or less established adaptations, such that today, the highest prevalences of O coincide with the most malaria-endemic areas [23]. A summary of this arms-race of adaptations is given in Fig. 1, with malaria’s strongholds prompting adaptive portfolios as diverse as their regions and founders.


Figure 1.  The great co-evolutionary race between malaria and man, dating back 200 million years.

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The diversity of malaria-adaptive mutations converges on the Erythrocyte

Common to most malaria-adaptive mutations is their effect on the red cell [24], which is the key body invaded and pathologically altered by Plasmodia and other convergently evolving [25] ‘apicomplexan haemoparasites’ such as Babesia and Theileria [26]. Erythrocytes may be an appealing sanctuary because, having shed their nuclei, they no longer intrinsically express HLA [27], and thus do not betray their invaders with antigen presentation. Erythrocytes also circulate by the billions to every tissue, including the skin where the female Anopheline mosquito serves as the vector to inject asexual malarial sporozoites into the human host. The unwelcome deposit is traded for a blood meal and the possibility of syphoning back sexual malarial gametocytes to complete the Plasmodium life cycle in the mosquito’s gut. In the host, the sporozoite takes asymptomatic root in the liver (hepatic schizogony) to release the merozoites responsible for invading erythrocytes [28]. The merozoites establish the deadly and iterative erythrocytic phase of infection, wherein ring forms (trophozoites) multiply until the maturely parasitized schizont ruptures to release 1–3 dozen merozoites committed to the next wave of invasion.

One approach to clinically arresting malaria is to block invasion of the erythrocyte entirely. With the portal of entry for Plasmodium vivax exclusively being the Duffy Antigen Receptor for Chemokines (DARC) [29], the most effective and prevalent [30] adaptation is the erythrolineage-specific loss of its expression through a GATA1 promoter mutation [31]. In contrast, the invasion ligands for P. falciparum range less specifically across the glycophorin sialoglycoproteins [32–34]. Glycophorin variants (e.g. glycophorin A-negativity [En(a-) phenotype], glycophorin B-negativity [S-s-U- phenotype], a glycophorin B/A tandem hybrid [Dantu phenotype], combined glycophorin A- and B-negativity [MkMk phenotype], post-translationally modified glycophorin [Tn or Cad phenotype] and glycophorin C-negativity [Ge- phenotype]) may be differentially resistant to invasion, but this resistance is rarely complete [35], and an epidemiologic proof of success analogous with that of African Duffy loss for P. vivax is lacking.

Humans have instead responded with a counter-attack directed at modifying the severity of the erythrocytic phase of infection, so that we find genetic differences not so much between those who do and do not have infection, but instead between those with uncomplicated vs. severe (fatality-bound) outcomes. One can speculate how a host might defend against total erythrocytic occupation after inexorable invasion, as illustrated in Fig. 2.


Figure 2.  Options in adapting to Plasmodium falciparum malaria.

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The best appreciated adaptations against P. falciparum, which differs as a species from any of the other four known to infect humans (P. vivax, P. ovale, P. malariae and now P. knowlesi [36]), are measures to address its undiscriminating if not potentially limitless erythrocyte infectivity [37]. Because the spleen is a key organ for recognizing and removing erythrocytes deemed unsatisfactory for the challenges of circulation, clinically imperceptible reductions in erythrocyte fitness can synergize with the earliest stages of erythrocyte infection to promote their sooner clearance. The ‘fitness hypothesis’ [38,39] explains how such disparate red cell polymorphisms might each attenuate high burdens of parasitemia at the nexus of the spleen, which recognizes a variety of non-specific signals [40] ranging from sinusoid-impassable stiffness, stigmata of oxidative or ultrastructural damage with hemichrome formation and band 3 aggregation, ‘eryptotic’ (erythrocyte programmed cell death) externalization of negatively charged phospholipids, and senescent neoantigen sensitization by autoantibodies and complement. These innate mechanisms are all that an immunologically naïve host may have available before parasite-specific adaptive immunity is established, and thus any trait which enhances these mechanisms is expected to be highly selected for in those populations coping with infections as notoriously fatal to children as P. falciparum malaria is [41,42].

The significance of the spleen can also be appreciated by the increased risk of severe or fatal malaria infection in asplenia [43,44]. It is only by surviving the primary infection that the adaptive power of the immune system can be witnessed, with the ‘premunition’ of seasoned hosts capable of tolerating various endemic burdens of recurrent or chronic low-grade parasitemia without fever [45,46]. The lack of superior adaptive immunity or the grace of sufficient innate immunity to overcome primary infections may equally explain why children under the age of 5  account for 90% of all malaria deaths in Africa [47].

Plasmodium falciparum as the most malignant of the malarias

  1. Top of page
  2. Abstract
  3. ‘Arms-race’ evolution between malaria and man
  4. Plasmodium falciparum as the most malignant of the malarias
  5. The ABO blood group system and P. falciparum malaria: evidence for selection pressures against Group A antigens, rather than for the mutant O isohaemagglutinins
  6. Acknowledgements
  7. Disclosures
  8. References


With such a large catalogue of red cell polymorphisms capable of limiting parasitemia through enhanced splenic clearance of infected erythrocytes [IE], it is no surprise that P. falciparum has counter-evolved a means by which to prevent their very traffic towards the spleen. Cytoadherence is the process by which IE arrest their flow in the pre-capillary venules and microvasculature. This phenomenon technically reduces the parasite’s death rate [with IEs remaining in relatively phagocytosis-free sanctuaries) and increases its birth rate (with IEs in close approximation with other immobilized uninfected erythrocytes (UE)] [48], but at the significant price of regional hypoperfusion in the host. This cytoadherence is achieved by remodelling of the IE membrane, upon which 500–7500 knob-like structures visibly erupt [49,50], with each bearing a parasite-encoded 200–350- kDa adhesion molecule known as Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) [51,52]. Interestingly, it appears that the origins of this virulence factor occurred even before P. falciparum made the speciation-split from P. reichenowi, although the split which led to today’s form may have occurred as recently as 10 000 [10–12] rather than 10 000 000 years ago [3,4].

Cytoadherence can manifest itself on the endothelium or in the lumen of microvessels. IE adherence to the microvascular endothelium is known as ‘sequestration’ [53], and IE adhesion to other uninfected circulating peripheral blood cells is known as ‘rosetting’ [54–56]. IE sequestration on the endothelium may either be direct [57–59] or indirect via IE-platelet adhesion through von Willebrand factor [60–62]. Potentially occlusive lumenal rosettes consist of IEs surrounding themselves with other UE [63] and/or platelets [64], perhaps rendering PfEMP1-studded IEs invisible once again to the pattern recognition motifs (PRMs) of the innate cellular immune system and/or to an affinity-matured adaptive humoral immune response. CD36 is an example of an innate monocyte/macrophage scavenger receptor which recognizes conserved motifs on PfEMP1 for the non-opsonic phagocytosis of IEs, while also being a key host cytoadherence ligand on endothelial cells (promoting sequestration) and on platelets (promoting rosetting) [65].

Being stickiest near the point of schizont rupture would seem to have two deliberate benefits for the parasite: assurance that vulnerable UEs are immediately nearby to facilitate invasion by emerging merozoites, and hiding those IEs which have invested so much in spawning the largest number of merozoites that can be gleaned from a spent erythrocyte. Indeed, the density of PfEMP1 is IE-stage and thus merozoite-load dependent [66], and it is this proportionality which accounts for the low sensitivity of blood film examination [67] in this most dangerous form of malaria. The mature IE forms (i.e. morphologically obvious schizonts) are thus rarely seen on smears prepared from phlebotomy specimens which rheologically select for those UE and early ring-form IEs still flowing in venous or capillary blood.

Cytoadhesivity is an appealing if not well-accepted explanation for the distinguished pathogenicity of P. falciparum [68,69]. Pathologic studies have shown a correlation between cytoadhesion and the severest manifestations of malaria [70–77]. Where associations are not so strong [57,71,78–80], sampling bias of least-adhesive clones may have occurred [81].

If cytoadhesion is in fact playing the predominant role in human malarial lethality, then host adaptations to reduce the expression of cytoadhesion ligands, or to differentially express them away from a disadvantageous to an advantageous cell (e.g. phagocyte) or neutral site (e.g. integument), are anticipated. It is in both the host’s and the vector’s common interest to distribute as much parasitemia peripherally as possible, so that gametocytes may easily return to the mosquito proboscis, while keeping the IE far removed from a host’s vital organs. Matched diversity at this lock-and-key interface of cytoadhesion is yet another clue to how essential this relationship is in the survival of either party.

The promiscuous and variable lectin-like domain

The centrality of PfEMP1 to the parasite’s successful evolution is underscored by the greater number and variability of its genes than those transcribing effectors of invasion [82,83]. The 50–60 genes encoding PfEMP1 in all its forms are members of the var family, and recombinant paralogs of the first exon account for a tremendous diversity of transcripts with their own binding properties [84]. The two key domains in the N-terminal head structure which benefit from this versatility and which are exposed on the IE to engage in host binding are the Duffy binding-like [DBL (α–ε)] domain and the cysteine-rich inter-domain region [CIDR (ε–γ)] [52]. Variable numbers of DBL and one to two CIDR domains define any given PfEMP molecule [85].

The DBL1 domain of PfEMP1 is lectin-like, in that it binds to a number of carbohydrate structures [86]. DBL1α(1) is a rosetting ligand which binds preferentially to the A antigen in the ABO system (‘1α’) and to CR1 (CD35) (‘1α1’) on UEs. DBL1α is also a sequestration ligand which binds to heparan sulphate-like glycosaminoglycans (HS-GAG) on the endothelium [87]. The CIDR domain is responsible for binding to CD36 (both the platelet rosetting and dominant endothelial sequestration ligand), as well as CD31 (PECAM-1) and IgM. Taken together, a single PfEMP-studded knob can have the power to bind numerous host determinants [88].

The ABO blood group system and P. falciparum malaria: evidence for selection pressures against Group A antigens, rather than for the mutant O isohaemagglutinins

  1. Top of page
  2. Abstract
  3. ‘Arms-race’ evolution between malaria and man
  4. Plasmodium falciparum as the most malignant of the malarias
  5. The ABO blood group system and P. falciparum malaria: evidence for selection pressures against Group A antigens, rather than for the mutant O isohaemagglutinins
  6. Acknowledgements
  7. Disclosures
  8. References

The blood groups of the ABO histocompatibility system are defined by the presence or absence of the co-dominantly expressed A or B sugars on various cell surfaces [89], as well as in terms of a ‘reverse type’ of plasma isohaemagglutinins raised against the lacking reciprocal sugar(s) which are then observed in the acquired aerodigestive microbiome [90]. The earliest theories on an ABO effect in malaria were drawn from observations that the infecting P. falciparum sporozoite expressed A-like sugars [91,92], such that those with naturally occurring anti-A would be expected to neutralize sporozoites at the point of skin injection, thereby altogether preventing the onset of the infectious disease itself [93]. However, there is no evidence that group O individuals suffer from fewer episodes of malaria [94].

An ABO effect that is relevant in disease severity and mortality, instead of in disease incidence, is therefore a legitimate consideration. With respect to the lectin-like action of PfEMP1, there can be no system more appealing than ABO for cytoadhesion options (Fig. 3). The UEs with which IEs rosette express ABO antigens at a density of a million sites per cell [95], and ABO antigens are also expressed on the platelets with which IEs rosette [89], as well as on the endothelium and/or its macromolecules (including vWF [96]) through which IEs sequester.


Figure 3.  Models for ABO Effects in Plasmodium falciparum Malaria Infection. EC, endothelial cells; IE, PfEMP-bearing infected erythrocytes; Le, Lewis blood group; PLT, platelets; Se, secretor blood group status; UE, uninfected erythrocytes.

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In vitro evidence supports that group A erythrocytes rosette more than O cells do [75,76,86,97–100] and that the A-attributed rosetting effect is abrogated with enzymatic conversion to O [97] or inhibited by free A antigen [86,97]. If ABO plays a role in mortality by this rosetting, then malaria may select against A and select for mutations achieving alternate histo-groups [101,102] from its glycosyltransferase. There may indeed be a spectrum of rosetting phenotypes between A and O; AO heterozygotes, weaker A subgroups and group B or AB types may lie somewhere in between [95]. Furthermore, if rosetting can be disrupted by competitive free A antigens, then those A phenotypes which also secrete the highest levels of free A antigens, such as Lewis (a-b-) [103] and/or Secretor-positive [104] individuals, might also enjoy a selection advantage, and perhaps even mitigate the survival disadvantage (or explain the persisting prevalence) of group A individuals. In support of this hypothesis, the geographic distributions for O, non-A, A2, weak A subgroups and high secretion phenotypes are each more frequent throughout malaria-plagued parts of the world [23,105].

Finally, although the most compelling evidence for malaria’s differential selective force on ABO through mortality has not yet been demonstrated, retrospective studies throughout Africa and India, powered to examine the next best surrogate of disease severity, have consistently demonstrated a statistically significant effect [100,106–110]. In Fig. 4, the disadvantageous effect of being A vs. non-A, and the advantageous effect of being O vs. non-O are shown in Forest plots [Comprehensive Meta-Analysis software, version 2, (Biostat™, Englewood, New Jersey, USA)].


Figure 4.  Clinical studies on the relationship between ABO and malaria severity: odds ratios for severe disease according to blood groups (Wild-type A vs. non-A and Mutant O vs. non-O). CI, confidence interval; H/CNS, hepatic dysfunction (jaundice) or central nervous system disturbance; OR, odds ratio; PM, placental malaria; SM, severe malaria.

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CR1 (CD35) polymorphisms and P. falciparum malaria: selection pressures for and against expression

CR1 (CD35) bears the nine antigens of the Knops blood group system and is not only a glycosylated antigen receptor for complement C3b with a highly variable normal range of expression (50–1200 copies/erythrocyte), but also a rosetting ligand of PfEMP1 [111]. Knops polymorphisms and the Helgeson (Knops-null) phenotypes, more common in malaria-endemic areas [22], may, like the group O type, minimize host UE rosetting potential. However, reduced expression of CD35 incurs the risk of reduced complement inhibition and thus more complement-dependent haemolysis, given its role in regulating complement and phagocytic clearance of immune complexes [112]. In hyperendemic areas where the burden of severe malarial anaemia and its attributable mortality are high, there may be a drive to increase expression [113], whereas in (usually seasonally endemic) areas where the total and mortal burden of cerebral (cytoadhesive) malaria tends to be higher, the drive may be towards lower expression [114–117].

Future directions and implications

Malaria still claims the life of a child every 30 s, and even under ideal therapeutic conditions, deaths nevertheless occur within 24 h of severe presentations [118]. There is still no antimalarial which redresses parasite-attributable changes already made to the IE [119], and thus the ultimate but impractical success of drugs may depend upon administration before cytoadhesive pathogenesis begins. Insights from blood group immunobiology and evolutionary genetics speak to the paramount nature of cytoadhesion. We eagerly await the results of the first prospective study powered to characterize the impact of ABO on malaria mortality [see Cytoadherence in Paediatric Malaria (CPM) Study, NCT 00707200 on]. Emerging proof of the role host blood group status in malaria mortality may urge complementary therapeutic strategies designed to limit cytoadhesion, with blood transfusion tactics more readily available than new designer drugs and vaccines. Options in transfusion medicine, from the use of group O blood to PfEMP-inhibitory A substance, may one day be evaluated, and if proven effective, offer fresh hope in counter-acting this age-old scourge.


  1. Top of page
  2. Abstract
  3. ‘Arms-race’ evolution between malaria and man
  4. Plasmodium falciparum as the most malignant of the malarias
  5. The ABO blood group system and P. falciparum malaria: evidence for selection pressures against Group A antigens, rather than for the mutant O isohaemagglutinins
  6. Acknowledgements
  7. Disclosures
  8. References
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