Sialic acids and the evolution of P. falciparum

The glycoproteins and glycolipids in other great ape species contain N-glycolyl-neuraminic acid (Neu5Gc) as their primary sialic acid. Sometime after the divergence of the lineage leading to Homo, a deletion mutation inactivated the gene CMP-Neu5Ac hydroxylase (CMAH), which codes for the enzyme that catalyzes the synthesis of Neu5Gc from N-acetyl-neuraminic acid (Neu5Ac); because we lack this enzyme, our glycoproteins and glycolipids contain Neu5Ac rather than Neu5Gc. Several years ago, Ajit Varki, Pascal Gagneux, and their colleagues proposed that the loss of CMAH may have gone to fixation in the human population because it conferred resistance to malaria, and that P. falciparum became an important human pathogen after it gained the ability to recognize Neu5Ac (Martin et al. 2005). A recent report by Stephen Rich and his colleagues provides strong support for this hypothesis (Rich et al. 2009).

P. falciparum is closely related to P. reichenowi, the main malaria parasite of chimpanzees; until now, however, the relationship between these two species has not been clear. The availability of eight new isolates of P. reichenowi enabled Rich et al. to carry out a more extensive phylogenetic analysis of the two plasmodium species than had previously been possible. P. reichenowi is much more genetically diverse than P. falciparum. All P. falciparum strains that are now circulating in humans apparently originated from P. reichenowi, possibly from a single cross-species transfer. The origin of P. falciparum cannot yet be accurately dated (estimates range between 10,000 and 3 million years ago). Clearly, however, P. falciparum and P. reichenowi did not co-speciate with their primate hosts; instead, P. falciparum arose from P. reichenowi long after the human and chimpanzee lineages diverged.

The invasion of red blood cells by P. reichenowi and P. falciparum depends on the interaction of erythrocyte-binding antigen (EBA)-175 on malaria merozoites with glycophorin A, a sialic acid-containing glycoprotein on the surface of erythrocytes. EBA-175 from P. reichenowi recognizes glycophorin A containing Neu5Gc but not glycophorin containing Neu5Ac; as a result, P. reichenowi is not a human pathogen. In contrast, P. falciparum EBA-175 binds to Neu5Ac-containing glycophorin A. Thus, it is likely that the inactivation of CMAH did indeed spread in early human populations because the loss of Neu5Gc conferred resistance to P. reichenowi or an ancestral plasmodium that also recognized Neu5Gc. Sometime later, a mutation that enabled P. reichenowi to recognize Neu5Ac led to the evolution of P. falciparum.
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The carbohydrate moieties of glycoproteins and glycolipids commonly serve as binding sites for pathogens. We should be prepared to find that host-pathogen co-evolution often leads to changes in these carbohydrates.

References

Martin MJ, Rayner JC, Gagneux P, Barnwell JW, Varki A. Evolution of human-chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12819-24.

Rich SM, Leendertz FH, Xu G, LeBreton M, Djoko CF, Aminake MN, Takang EE, Diffo JL, Pike BL, Rosenthal BM, Formenty P, Boesch C, Ayala FJ, Wolfe ND. The origin of malignant malaria. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14902-7.