The origin of malignant malaria

Abstract

Plasmodium falciparum, the causative agent of malignant malaria, is among the most severe human infectious diseases. The closest known relative of P. falciparum is a chimpanzee parasite, Plasmodium reichenowi, of which one single isolate was previously known. The co-speciation hypothesis suggests that both parasites evolved separately from a common ancestor over the last 5-7 million years, in parallel with the divergence of their hosts, the hominin and chimpanzee lineages. Genetic analysis of eight new isolates of P. reichenowi, from wild and wild-born captive chimpanzees in Cameroon and Côte d'Ivoire, shows that P. reichenowi is a geographically widespread and genetically diverse chimpanzee parasite. The genetic lineage comprising the totality of global P. falciparum is fully included within the much broader genetic diversity of P. reichenowi. This finding is inconsistent with the co-speciation hypothesis. Phylogenetic analysis indicates that all extant P. falciparum populations originated from P. reichenowi, likely by a single host transfer, which may have occurred as early as 2-3 million years ago, or as recently as 10,000 years ago. The evolutionary history of this relationship may be explained by two critical genetic mutations. First, inactivation of the CMAH gene in the human lineage rendered human ancestors unable to generate the sialic acid Neu5Gc from its precursor Neu5Ac, and likely made humans resistant to P. reichenowi. More recently, mutations in the dominant invasion receptor EBA 175 in the P. falciparum lineage provided the parasite with preference for the overabundant Neu5Ac precursor, accounting for its extreme human pathogenicity.

Fig. 1.

Alternative hypotheses for the origin of P. falciparum as a human parasite. Green- and blue-shaded areas correspond to parasites infecting chimpanzee and human hosts, denoted as C and H, respectively. The hypothetical ancestors are denoted as F (for P. falciparum), R (for P. reichenowi), and RF (for their common ancestor). (Left) Parasites of humans and chimpanzees diverged as their respective hosts did, starting 5–7 million years ago (5, 52). Alternatively, a human parasite lineage could have given rise to the chimpanzee lineage (Center), or vice versa (Right). The present data overwhelmingly support the latter alternative, identifying chimpanzees as the ancestral host for the agent of malignant human malaria.

Fig. 2.

Circumsporozoite surface protein (Csp) repeat composition of several Plasmodium species showing that repeat units of Csp genes are diagnostic of species type (24). All characteristic Csp amino acid repeats of P. falciparum, including NVDP and NANP are also found in P. reichenowi. Some P. reichenowi alleles show additional repeat types (NADP and NP).

Fig. 3.

Pairwise nucleotide polymorphism (π) at three genetic loci—cytB, clpC, and 18S rRNA—among Plasmodium species (see SI Text). Diversity in malaria parasites is estimated for (i) P. falciparum isolates alone, (ii) P. reichenowi isolates alone, (iii) P. falciparum + P, reichenowi, and (iv) P. falciparum + P. reichenowi + P. vixax. The addition of P. vivax significantly inflates estimates of nucleotide variation (π), which is consistent with the evolutionary independence of P. vivax. The addition to P. reichenowi of the nucleotide polymorphism found in a very large sample of 133 P. falciparum isolates does not substantially increase the polymorphism found in P. reichenowi alone.

Fig. 4.

Cytochrome B gene (cytB) phylogeny of nine P. reichenowi strains (eight newly discovered plus the previously known CDC1 strain) together with a global representation of P. falciparum (133 strains), as well as representative Plasmodium species of rodent and avian parasites. The new P. reichenowi strains are designated by the name of the host chimpanzee from which they were isolated. Three isolates are from Côte d'Ivoire (two Rafiki and Loukoum), the other five are from Cameroon. Multiple strains with identical sequences occur on each of several terminal branches of P. falciparum and other Plasmodium species (n = number of strains). Terminal branches with multiple strains are superscripted; associated GenBank accession numbers for all sequences are included in Table S1. Two distinct nucleotide sequences were identified from Rafiki, and are arbitrarily labeled 1 and 2. The numbers at the nodes are bootstrap support; above the node is support from maximum parsimony whereas the number below indicates maximum likelihood support (no number at a node indicates <50% support for that node).