Evolution of human-chimpanzee differences in malaria susceptibility: Relationship to human genetic loss of N -glycolylneuraminic acid

Abstract

Chimpanzees are the closest evolutionary cousins of humans, sharing >99% identity in most protein sequences. Plasmodium falciparum is the major worldwide cause of malaria mortality. Plasmodium reichenowi, a morphologically identical and genetically very similar parasite, infects chimpanzees but not humans. Conversely, experimental P. falciparum infection causes brief moderate parasitization and no severe infection in chimpanzees. This surprising host specificity remains unexplained. We modified and enhanced traditional methods for measuring sialic acid (Sia)-dependent recognition of glycophorins by merozoite erythrocyte-binding proteins, eliminating interference caused by endogenous Sias on transfected cells, and by using erythroleukemia cells to allow experimental manipulation of Sia content. We present evidence that these remarkable differences among such closely related host-parasite pairs is caused by species-specific erythrocyte-recognition profiles, apparently related to the human-specific loss of the common primate Sia N-glycolylneuraminic acid. The major merozoite-binding protein erythrocyte-binding antigen-175 of P. falciparum apparently evolved to take selective advantage of the excess of the Sia N-acetylneuraminic acid (the precursor of N-glycolylneuraminic acid) on human erythrocytes. The contrasting preference of P. reichenowi erythrocyte-binding antigen-175 for N-glycolylneuraminic acid is likely the ancestral condition. The surprising ability of P. falciparum to cause disease in New World Aotus monkeys (geographically isolated from P. falciparum until arrival of peoples from the Old World) can be explained by parallel evolution of a human-like Sia expression pattern in these distantly related primates. These results also have implications for the prehistory of hominids and for the genetic origins and recent emergence of P. falciparum as a major human pathogen

African apes as reservoirs of Plasmodium falciparum and the origin and diversification of the Laverania subgenus

“…These evolutionary changes would account for the reduced virulence of P. falciparum in apes and the presumed similar reduced virulence of P. reichenowi in humans. These two-way attenuations of virulence are consistent with the specific binding activities demonstrated by Martin et al (16). The enhanced specificity of falciparum EBA-175 for the human Sia Neu5Ac (rather than for the ape Sia Neu5Gc) indicates that P. falciparum evolved in association with the hominid lineage, rather than in chimpanzees, bonobos, or gorillas.…”

“…Even after splenectomy to increase parasite survival, experimentally infected chimpanzees did not develop a parasitemia equivalent to that observed in humans (33,34). The strong human specificity of P. falciparum may be due to species-specific erythrocyte recognition profiles (16,17). The mutational loss of the common primate Sia Neu5Gc may have protected our human ancestors from P. reichenowi.…”

“…The scarcity of neutral polymorphism was explained as the result of a recent world expansion of P. falciparum-the Malaria's Eve hypothesis (8)-which was estimated to have happened starting a few thousand years ago, rather than millions of years ago, as expected according to the cospeciation hypothesis. Martin et al (16) suggested a mechanism compatible with a relatively recent origin of P. falciparum from P. reichenowi based on the differential expression of host sialic acid (Sia) ligands that populate the surface of erythrocytes and other cells, and on differences in Sia-binding preferences among parasite receptors. A mutation in the human lineage inactivated the CMAH gene rendering human ancestors unable to generate the Sia Neu5Gc from its precursor NeuAc, thus making humans resistant to P. reichenowi.…”

“…A mutation in the human lineage inactivated the CMAH gene rendering human ancestors unable to generate the Sia Neu5Gc from its precursor NeuAc, thus making humans resistant to P. reichenowi. A later mutation in the dominant invasion receptor EBA175 provided the P. falciparum lineage with preference for the overabundant Neu5Ac precursor, accounting for its extreme human pathogenicity (16,17). Rich et al (18) have recently analyzed, in eight new isolates of P. reichenowi, gene fragments from the three principal genomes of Plasmodium parasites, mitochondrial (cytB), apicoplast (clpC), and nuclear (18S rDNA).…”

MARveling at parasite invasion

“…More remarkable is how the differences in sialic acids may be selectively exploited during parasite recognition of its host 17 . For example, the Plasmodium species that infects chimpanzees, P. reichenowei, preferentially binds to N-glycolylneuraminic acid (Neu5Gc), the predominant sugar on chimp erythrocytes 15,18,19 . By contrast, the human pathogen, P. falciparum, displays a marked predilection for the metabolic precursor of Neu5Gc, Neu5Ac 19 .…”