Human-specific evolution of sialic acid targets: Explaining the malignant malaria mystery?

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Abstract
Malaria caused by Plasmodium falciparum (“malignant malaria”) is one of the most devastating pathogens of humans (1). Plasmodium reichenowi , which infects chimpanzees and gorillas, is the closest relative of P. falciparum (2). In early 20th-century experiments (never to be replicated), blood from P. reichenowi -infected chimpanzees was injected into humans, but failed to produce infections (3). Conversely, chimpanzees injected with P.falciparum -infected human blood suffered no in fection. Taken together, these data suggested that each parasite had coevolved with its host, but did not rule out chimpanzee to human transmission, or vice versa. In this issue of PNAS, Rich et al. (4) provide an answer to this malignant malaria “mystery” and confirm a prediction that we and our colleagues made earlier (5). Several Anopheles mosquito species mediate the P. falciparum life cycle (6, 7). After an infected mosquito bite, the injected sporozoites infect host liver cells, generating merozoites that invade circulating erythrocytes (RBCs). Bouts of high fever follow when merozoites undergo cycles of asexual reproduction in RBCs. P. falciparum expresses multiple binding proteins that recognize specific targets on RBCs.* The major targets are terminal sialic acids (Sias) on O-linked glycan chains attached to glycophorins, the most abundant RBC surface glycoproteins. Although Sia-independent RBC invasion is known (8), most field isolates exhibit Sia dependency for RBC binding (9). Fig. 1. Proposed scenario for evolution of human and great ape malarias. The scenario accounts for most of the relevant facts and includes some speculation. Sias are a family of sugars found at the outer termini of cell surface glycan chains of all cells of all vertebrates (10). Although Sias appear essential for development, they are also targets for many pathogens (10). Thus, the host “sialome” must constantly evolve to evade rapidly evolving pathogens. For example, an Alu -mediated exon deletion … 1To whom correspondence may be addressed. E-mail: a1varki{at}ucsd.edu or pgagneux{at}ucsd.edu