Prehistory of falciparum malaria

Martin and colleagues (2005) have a PNAS paper examining the coevolution of falciparum malaria (Plasmodium falciparum) with early humans.

The closest relative of P. falciparum is P. reichenowi, which infects chimpanzees but not humans. The study finds that the difference between these parasites is in their mechanism for attacking red blood cells:

P. falciparum and P. reichenowi are two morphologically indistinguishable Plasmodium species that nevertheless exhibit strong host preferences for humans and chimpanzees, respectively (11, 12, 15). Recent phylogenetic sequence studies have confirmed the genetic distinctness of these species. However, no comparative functional studies had been done until now. From the present experiments, we conclude that the strong host species preferences of P. falciparum and P. reichenowi could be explained on the basis of differences in host erythrocyte Sias. Our data show not only that PfEBA-175 prefers Neu5Ac but also that Neu5Gc interferes with this binding, likely explaining why P. falciparum is unable to successfully infect healthy chimpanzees. Conversely, PrEBA-175 strongly prefers Neu5Gc, perhaps explaining why P. reichenowi failed to infect human subjects in old studies (11, 12). The impact of merozoite invasion ligands on host species specificity has been confirmed recently in the simian malaria, Plasmodium knowlesi, in which knockout of P. knowlesi DBP-, an invasion ligand related to EBA-175, renders that parasite unable to invade human erythrocytes (53).

They corroborate the hypothesis by showing that Aotus monkeys, which can also host P. falciparum, has evolved the human-like Neu5Ac on their blood cells.

The bottom line is that the original loss of Neu5Gc in humans probably was a malaria defense, dating to around 3 million years ago. Later, a new strain of Plasmodium evolved the capacity to attack Neu5Ac effectively; this strain became today's P. falciparum.


Martin MJ, Rayner JC, Gagneux P, Barnwell JW, Varki A. 2005. Evolution of human-chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc Nat Acad Sci USA 102:12819-12824. Full text online