Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax

Abstract

Plasmodium falciparum and Plasmodium vivax account for more than 95% of all human malaria infections, and thus pose a serious public health challenge. To control and potentially eliminate these pathogens, it is important to understand their origins and evolutionary history. Until recently, it was widely believed that P. falciparum had co-evolved with humans (and our ancestors) over millions of years, whilst P. vivax was assumed to have emerged in southeastern Asia following the cross-species transmission of a parasite from a macaque. However, the discovery of a multitude of Plasmodium spp. in chimpanzees and gorillas has refuted these theories and instead revealed that both P. falciparum and P. vivax evolved from parasites infecting wild-living African apes. It is now clear that P. falciparum resulted from a recent cross-species transmission of a parasite from a gorilla, whilst P. vivax emerged from an ancestral stock of parasites that infected chimpanzees, gorillas and humans in Africa, until the spread of the protective Duffy-negative mutation eliminated P. vivax from human populations there. Although many questions remain concerning the biology and zoonotic potential of the P. falciparum- and P. vivax-like parasites infecting apes, comparative genomics, coupled with functional parasite and vector studies, are likely to yield new insights into ape Plasmodium transmission and pathogenesis that are relevant to the treatment and prevention of human malaria.

Keywords: African apes; Evolution; Laverania; Malaria; Plasmodium falciparum; Plasmodium vivax; Zoonotic transmission.

Fig. 1

Evolutionary relationships of Plasmodium spp. Colors highlight Plasmodium spp. that infect humans (red), chimpanzees (blue) and gorillas (green). Four groups of Plasmodium spp. are shown, with subgenus designations indicated for primate parasites. The phylogeny was estimated by maximum likelihood analysis of 2.4 kb of the mitochondrial genome; the scale bar indicates 0.03 substitutions per site.

Fig. 2

Geographic distribution of (A) Laverania and (B) Plasmodium vivax infections in wild-living apes. Field sites are shown in relation to the ranges of the four subspecies of the common chimpanzee (inset: Pan troglodytes verus, black; Pan troglodytes ellioti, purple; Pan troglodytes troglodytes, magenta; Pan troglodytes schweinfurthii, blue), the Cross River (Gorilla gorilla diehli, yellow stripe), western lowland (Gorilla gorilla gorilla, red stripe), and eastern lowland (Gorilla beringei graueri, cyan stripe) gorilla, as well as the bonobo (Pan paniscus, orange) in sub-Saharan Africa (Caldecott and Miles, 2005). Field sites are labeled by a two-letter code as previously reported (Liu et al., 2010a, 2014) or numbers (Boundenga et al., 2015), and those where ape malaria was detected are highlighted in yellow, with black, green or red lettering indicating that chimpanzees, gorillas, or both were infected. Triangles denote ape rescue centers and asterisks mosquito collection sites. Circles, squares and hexagons identify locations where fecal samples were collected from chimpanzees, gorillas or both species, respectively. Ovals indicate bonobo sites. At the TA and KB sites, blood and tissue samples were obtained from injured or deceased habituated chimpanzees (Kaiser et al., 2010; Krief et al., 2010; De Nys et al., 2013). Diamonds in (B) indicate the capture sites of ape P. vivax infected sanctuary chimpanzees (black border) and gorillas (green border), respectively, and a star denotes the location where a European forester became infected with ape P. vivax (Prugnolle et al., 2013). Data were compiled from published (Kaiser et al., 2010; Liu et al., 2010a, 2014, 2016; De Nys et al., 2013; Paupy et al., 2013; Prugnolle et al., 2013; Boundenga et al., 2015) and unpublished studies (Table 1). The full names and locations of all sites are provided in Supplementary Table S1.

Fig. 3

Evolutionary relationships of ape and human Laverania parasites. The phylogenetic relationships of (A) mitochondrial cytochrome B (cytB; 956 bp) and (B) nuclear lactate dehydrogenase (ldh; 772 bp) gene sequences, as well as (C) concatenated mitochondrial protein (CoxI/CoxIII/CytB; 981 amino acids) sequences are shown. Ape parasite sequences are colored according to their host species (Pan troglodytes verus, light blue; Pan troglodytes troglodytes, red; Pan troglodytes schweinfurthii, dark blue; Pan troglodytes ellioti, orange; Gorilla gorilla gorilla, green), and human parasite reference sequences are shown in black. A black circle denotes the Plasmodium reichenowi PrCDC reference sequence (Otto et al., 2014) derived from a chimpanzee captured in the Belgian Congo (now the Democratic Republic of the Congo) (Pan troglodytes schweinfurthii) (Coatney et al., 1971). (C) Four Plasmodium falciparum sequences from captive bonobos (Krief et al., 2010) and one Plasmodium praefalciparum sequence from a captive greater spot-nosed monkey (Prugnolle et al., 2011) are shown in magenta and grey, respectively. Parentheses indicate Laverania spp. Phylogenies were generated using maximum likelihood methods. Asterisks at major nodes indicate bootstrap values ≥ 65%, and the scale bars represent (A, B) 0.01 nucleotide substitutions per site, or (C) 0.001 amino acid replacements per site, respectively. Sequences were combined from multiple studies (Kaiser et al., 2010; Krief et al., 2010; Liu et al., 2010a, 2016; Prugnolle et al., 2011).

Fig. 4

Evolutionary relationships of ape and human Plasmodium vivax parasites. Phylogenies were derived from (A) mitochondrial (mt)DNA fragment D (2,539 bp), (B) nuclear DNA (ldh gene; 711 bp), and (C) apicoplast DNA (clpM gene; 574 bp). Parasite sequences are colored according to their host species (Pan troglodytes troglodytes, red; Pan troglodytes schweinfurthii, dark blue; Pan troglodytes ellioti, orange; Gorilla gorilla gorilla, green; human, black); the red star denotes a parasite from a European person who worked in an African forest. Mosquito (Anopheles moucheti) derived sequences are shown in cyan (and denoted with ‘A’). Reference sequences for Plasmodium cynomolgi, Plasmodium inui, Plasmodium fragile and Plasmodium knowlesi are indicated. A lineage of parasite sequences from wild chimpanzees, which is related to ape and human P. vivax, likely represents a new Plasmodium sp. which has been designated Plasmodium carteri (black arrows). Phylogenies were generated using maximum likelihood methods. Asterisks at major nodes indicate bootstrap values ≥ 65%, and the scale bars represent 0.01 nucleotide substitutions per site. Sequences were combined from multiple studies (Krief et al., 2010; Paupy et al., 2013; Prugnolle et al., 2013; Liu et al., 2014).