Ape Plasmodium parasites as a source of human outbreaks

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1 REVIEW /j x Ape Plasmodium parasites as a source of human outbreaks L. Duval 1 and F. Ariey 2 1) Maladies Infectieuses et Vecteurs, Écologie, Génétique, Évolution et Contrôle, Institut de Recherche pour le Développement, Montpellier and 2) Unité d Immunologie Moléculaire des Parasites, Institut Pasteur de Paris, Paris, France Abstract Recent studies have revealed a remarkable molecular diversity of Plasmodium parasites in great apes in Africa, as well as parasite exchange events between these primates and humans. We review the different points of view proposed on the origin of human malaria, and discuss ape Plasmodium parasites as a source of human outbreaks. Keywords: Great apes, Laverania Plasmodium, non-laverania Plasmodium, non-human primates, outbreaks Article published online: 22 March 2012 Clin Microbiol Infect 2012; 18: Corresponding author: L. Duval, Maladies Infectieuses et Vecteurs, Écologie, Génétique, Évolution et Contrôle, Institut de Recherche pour le Développement, Montpellier, France linduval@yahoo.fr Introduction In the middle of the twentieth century, numerous experimental malarial infections were induced in humans (either by mosquito bites or by direct blood transfusion) to test the potential zoonotic character of malarial pathogens isolated from wild-living African chimpanzees and gorillas, and Asian non-human primates [1]. The ability of a species to infect humans in laboratory conditions is summarized in Table 1. It is worth noting that only a few species, all primates originating from Southeast Asia, were considered to be able to infect humans [1]. Today, molecular tools allow exploration of the diversity of wildlife haemosporidian parasites (i.e. the genera Plasmodium, Hepatocystis, etc.) [2 5]. Data collected in recent years have shown notable Plasmodium diversity in non-human primates, especially in African great apes [6,7]. Considering the current overall molecular phylogeny of haemosporidian parasites, it appears that human Plasmodium species are polyphyletic (Fig. 1) [8]. Thus, multiple switches between mammalian hosts are likely to explain the evolutionary history of human malarias [8,9]. As shown in mammalian hosts, host switches appear to be common phenomena in the evolution of malarial parasites [10 12]. On the basis of recent data included in the growing literature on this topic, we present here different hypotheses on malarial spread in human populations, and discuss the potential risk of ongoing or future outbreaks of ape malarial parasites in humans. Non-Laverania Plasmodium Before the successful eradication campaigns in the middle of the twentieth century, Plasmodium vivax, found as far as northern Europe, was the malarial parasite with the broadest geographical coverage [13]. Its impact on human health has been indirectly demonstrated by traces of selective pressures on the human genome, particularly on the Duffy blood group in African human populations and glucose-6-phosphate dehydrogenase deficiency in Asia [14,15]. P. vivax belongs to the monophyletic group of Plasmodium parasites infecting catarrhine monkeys in Southeast Asia [8,16]. It is generally accepted that it originated in humans as a consequence of host capture from macaques to hominids in Southeast Asia [17,18]. Interestingly, despite numerous studies on Plasmodium parasites infecting Southeast Asian primates (including the orangutan, the Asian great ape), none of them was found to be infected with P. vivax [19]. On the other hand, captive Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases

2 CMI Duval and Ariey Ape Plasmodium parasites 529 TABLE 1. Major Plasmodium species infecting primates, and their ability to infect humans [1] Species Natural host Origin P. cynomolgi Macaca species Southeast Asia Yes P. eylesi Gibbon Southeast Asia No P. gonderi Cercocebus species Africa No P. hylobati Gibbon Southeast Asia No P. jefferyi Gibbon Southeast Asia No P. pitheci Orangutan Southeast Asia? P. inui Macaca species Southeast Asia Yes P. coatneyi Macaca species Southeast Asia No P. knowlesi Macaca species Southeast Asia Yes P. reichnowi Chimpanzee Africa No P. girardi Lemur Madagascar? P. fieldi Macaca species Southeast Asia No Non-Laverania Laverania P. vivax group P. cynomolgi P. hilobati P. knowlesi P. gonderi P. malariae group P. ovale group P. malagasy P. vinkeia group Hepatocystis group African/Asian mammals P. reichenowi Chimpanzees P. falciparum P. praefalciparum P. billcollinsi P. blacklocki P. gaboni P. alderi Asian monkeys Asian monkeys Humans/Asian monkeys African monkeys Malagasy lemurs African rodents Chimpanzees Chimpanzees Infection in humans FIG. 1. Schematic phylogeny of mammal Plasmodium parasites, showing the polyphyly of human malarial parasites (in red). Unresolved nodes. and wild-living African gorillas and chimpanzees were recently found to be infected with a Plasmodium parasite with mitochondrial DNA similar to that of human P. vivax [7,20,21]. In 2003, Carter argued that P.vivax would have been isolated in human African populations during the late ice age between and years ago [22]. If this is the case, the P. vivax population currently observed in great apes could be the descendants of this ancient P. vivax lineage, which led to red blood cell (RBC) Duffy-negative selection in African human populations. Thus, the P. vivax cases described in non-african people returning from Africa might result from zoonotic ape transmission [23]. However, serological studies have demonstrated an immune response specific to P. vivax in West Central African populations, and molecular diagnosis evidence has confirmed the possibility of such infections in Duffy antigen-negative humans [24 26]. This strongly suggests that P. vivax exploits an alternative pathway to invade Duffy-negative RBCs. This stresses the need to determine the epidemiology of P. vivax throughout Africa and evaluate the capacity of new Duffyindependent P. vivax strains to emerge. Comparative surveys need to be performed in ape populations to evaluate their possible involvement in the emergence and spread of P. vivax in Africa. Plasmodium knowlesi, transmitted by the Anopheles leucosphyrus group, is a parasite that naturally infects primates belonging to the genus Macaca in Southeast Asia [1]. For the past 10 years, the increasing systematic use of relevant molecular malaria diagnosis has highlighted an impressive number of unsuspected human P. knowlesi infections. The first cases were detected in Malaysia and the Philippines [27,28]. Today, P. knowlesi is found infecting Thai, Vietnamese and Cambodian populations, for whom environmental anthropization overlaps with the natural geographical distribution of macaques [29 31]. Modifications of the wildlife population biogeography might favour close interactions and parasite exchanges. The question remains: is P. knowlesi spreading over Southeast Asia via interhuman exchanges as a new human outbreak, or only via macaques to human host switches? Furthermore, have these new human P. knowlesi infections originated recently, or are they simply more readily detected by molecular tools [32 34]? In Cambodia, it seems that the presence of this species in the human population is recent, and no macaques have yet been found to be infected with P. knowlesi [31]. This could argue for possible interhuman transmission. Considering that P. knowlesi has been responsible for fatal cases [35], and the possibility of P. knowlesi being transmitted by Anopheles stephensi, a widespread vector in Asia, particularly in the Indian subcontinent, this parasite is a serious candidate for a potential human outbreak [36 38]. It is paticularly urgent to implement containment and monitoring measures, in order to better characterize the transmission of this species to humans and propose appropriate control measures. Plasmodium schwetzi, which is morphologically similar to human Plasmodium ovale (or P. vivax), was originally described by Reichenow in 1920 in apes from Cameroon [1]. Experimental infections by P. schwetzi in humans have been reported [39], and in 1970 Contacos established its zoonotic potential in Africa [40]. Plasmodium rodhaini, another African great ape Plasmodium species, which is morphologically similar to human Plasmodium malariae, was considered to be an anthroponosis or a zoonosis of long standing [1]. On the basis of molecular data, it appears that chimpanzees can be infected with human P. ovale and P. malariae and maintain parasite infection for long periods [21,41,42]. They could

3 530 Clinical Microbiology and Infection, Volume 18 Number 6, June 2012 CMI contribute to continuous parasite exchanges of these two human malarial parasites in Africa. Furthermore, chimpanzees harbour a larger diversity of P. ovale-like and P. malariae-like parasites than humans [7,21,41]. A phylogeny inferred from mitochondrial molecular data points to a recent common ancestor of human P. ovale and P. malariae and those infecting chimpanzees. However, no related parasites have been found in gorilla hosts. Laverania Plasmodium Recent studies have revealed an unsuspected but remarkable molecular diversity of Laverania parasites in captive and wildliving great apes (gorillas, chimpanzees, and bonobos) in West and Central Africa [6,7,20,43 45]. Most of these studies, which significantly increased our knowledge of Plasmodium infections in wild apes, were based on new, noninvasive malarial parasite detection in faecal samples, allowing large-scale screening. On the basis of molecular, genetic and phylogenetic characteristics, Laverania parasites seemed to be, at this time, composed of at least six well-defined, closely related and host-specific clades. Rayner et al. [46] proposed for clarity that these six Laverania clades could correspond to six distinct ape Laverania species, named, respectively, Plasmodium reichenowi, Plasmodium gaboni and Plasmodium billcollinsi for chimpanzees (Pan troglodytes verus, Pan troglodytes ellioti, Pan troglodytes troglodytes, and Pan troglodytes schweinfurthii) and Plasmodium falciparum Plasmodium praefalciparum, Plasmodium adleri and Plasmodium blacklocki for malaria parasites specific to gorillas (Gorilla gorilla). These malarial species seem to be widely distributed in wild-living African ape populations, without geographical distinction, and with relatively high prevalence, as observed for P. falciparum infections in humans. Phylogeny inferred from mitochondrial Laverania parasite sequences revealed that parasitic exchange events between great apes and humans have occurred during their evolutionary history, leading to the divergence of P. falciparum in humans from that in gorillas [7,46], and making P. falciparum an ancient outbreak in humans [47 49]. More recently, a strain similar to P. falciparum has been reported in an African pet monkey (Cercopithecus nictitans) [50], and the authors argued that this finding challenged the gorilla origin of the human P. falciparum parasite (i.e. African non-ape primate origin). Unfortunately, this finding has been controversial, being not well enough supported by the data [51]. These potential host switches highlight, rather, a significant adaptive capacity of Laverania parasites to adapt to new, non-natural hosts. Until recently, it was assumed that P. falciparum and P. reichenowi (the only close relative of P. falciparum known and molecularly characterized) had evolved from a common ancestor parasite, independently in their respective hosts, humans and chimpanzees, as these two lineages have gradually diverged from one another over the last 5 7 million years, i.e. the co-speciation hypothesis. The new findings on malarial parasites in apes challenged this initial co-speciation hypothesis, suggesting an alternative hypothesis for the origin of the malignant human malarial parasite, i.e. a gorilla origin of human P. falciparum. On the basis of comparison of mitochondrial DNA sequences from human P. falciparum strains and malarial parasites closely related to human P. falciparum strains in gorillas, Baron et al. [47] subsequently revised the age estimates of P. falciparum infection in humans to between 1 million and years. Currently, P. falciparum appears to be the only Laverania parasite that is able to infect humans; experimental infections with P. reichenowi in humans have failed [1]. The invasion of RBCs by P. reichenowi and P. falciparum depends mostly on the interaction of erythrocyte-binding antigen -175 on malarial merozoites with glycophorins, which are sialic acid-containing glycoproteins on the surfaces of RBCs (Fig. 2). N-Glycolylneuraminic acid is a sialic acid expressed in apes and absent in human tissues, because of inactivation of the gene encoding CMP-N-acetylneuraminic acid hydroxylase [52,53]. Human DNA contains a 92-bp deletion, resulting in a frameshift mutation that prevents the production of N-glycolylneuraminic acid, and that leads to the accumulation of its precursor, N-acetylneuraminic acid (Neu5Ac). Both molecular and fossil explorations (Neanderthals did not have the enzyme needed to convert Neu5Ac) are congruent in indicating the time of appearance of this mutation to be around 2 million years ago [54]. It is hypothesized that Lavarania malaria could be the main selective pressure resulting in the fixation of this allele in the entire human population. A new Laverania parasite, able to use Neu5Ac to invade RBCs, is supposed to have emerged in human populations, leading to the well-known P. falciparum pathogen. The loss of hydroxylase activity induced by Laverania malarial parasites and the Duffy-negative antigen in African populations due to P. vivax selective pressure highlight the ongoing interactions between malarial parasites and humans during their evolutionary history. Large-scale sampling of wide-ranging African apes identified only P. falciparum-like parasites in western lowland gorillas [7]. In contrast, captive chimpanzees, living in close proximity to human populations, have been found to be infected with P. falciparum, highlighting their potential role as a reservoir for P. falciparum or the fact that they could be

4 CMI Duval and Ariey Ape Plasmodium parasites 531 FIG. 2. One of the main stages in the colonization of a new mammalian host is the ability of the parasite to multiply within its host, and, in the case of Plasmodium, to colonize the red blood cells. We can schematically describe two major pathways in the invasion of red blood cells: the Duffy antigen for parasites belonging to the Plasmodium vivax group, and glycophorin for parasites belonging to the subgenus Laverania. The evolutionary pressures induced by malarial infection on these two proteins are major. They are at the origin of the lack of expression of Duffy antigen chemokine receptor (DARC) in red blood cells of human populations in Africa, and may have driven the evolutionary history of Plasmodium falciparum, which remains the only Laverania species to infect humans. victims of anthroponosis [45]. In addition to chimpanzees, captive bonobos can also be infected with human P. falciparum strains (resistant to antimalarial drugs) [20]. The question arises of the forces that drive Laverania parasites and other Plasmodium parasites to be confined to a specific host or confer their ability to jump the species barrier and adapt to another host [55]. Captive chimpanzees living in African sanctuaries could represent a helpful model with which to better understand host parasite interactions, potential human ape and ape ape parasite exchanges, and parasite adaptation capacities. The hypothesis of a human malarial parasite reservoir in apes could be tested, as well as the pathogenicity of human malarial parasites and other Laverania parasites in great apes. This would be extremely relevant for malaria eradication programmes and ape conservation programmes [56]. Furthermore, the investigation of human populations sharing the same environmental constraints as chimpanzees and gorillas in nature with adequate molecular diagnostic tools is paramount to document potential cases of human malarial infections with ape malarial parasites. Conclusions Malaria is a well-known evolutionary force within the human genome [57]. For P. vivax and P. falciparum, which are both major public health concerns, there is convincing evidence of an origin from a parasite host exchange from non-human primates to humans. Now, the new capacity of P. vivax to invade Duffy-negative population needs to be confirmed and characterized across Africa. Also, the potential interhuman transmission of P. knowlesi in Southeast Asia has to be evaluated, in order for appropriate measures to be implemented. In Central Africa, the close contact between apes and humans, associated with the low level of control and monitoring of malaria in remote areas, could represent a risk and stimulate the emergence of another Laverania malarial parasite. The first priority is to enlarge surveys in this area, with adequate molecular diagnostic tools. Documenting the potential role of great apes and other non-human primates as reservoirs for human malarial parasites, and their capacity to harbour Plasmodium species able to switch to human populations, is important for future malarial eradication programmes. Transparency Declaration Conflicts of interest: nothing to declare. References 1. Coatney GR, Collins WE, Warren M et al. The primate malarias. Washington, DC: US Government Printing Office, Garnham PCC. Malaria parasites and other Haemosporidia. Oxford: Blackwell, Hellgren O, Waldenström J, Bensch S. A new PCR assay for simultaneous studies of Leucocytozoon, Plasmodium, and Haemoproteus from avian blood. J Parasitol 2004; 90: Megali A, Yannic G, Christe P. Disease in the dark: molecular characterization of Polychromophilus murinus in temperate zone bats revealed a worldwide distribution of this malaria-like disease. Mol Ecol 2011; 20: Putaporntip C, Jongwutiwes S, Thongaree S et al. Ecology of malaria parasites infecting Southeast Asian macaques: evidence from cytochrome b sequences. Mol Ecol 2010; 19: Rich SM, Leendertz FH, Xu G et al. The origin of malignant malaria. Proc Natl Acad Sci USA 2009; 106: Liu W, Li Y, Learn GH et al. Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 2010; 467: Escalante AA, Freeland DE, Collins WE et al. The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome. Proc Natl Acad Sci USA 1998; 95: Garamszegi LZ. Patterns of co-speciation and host switching in primate malaria parasites. Malar J 2009; 8: Duval L, Robert V, Csorba G et al. Multiple host-switching of Haemosporidia parasites in bats. Malar J 2007; 6: Hayakawa T, Culleton R, Otani H et al. Big bang in the evolution of extant malaria parasites. Mol Biol Evol 2008; 25: Martinsen ES, Perkins SL, Schall JJ. A three-genome phylogeny of malaria parasites (Plasmodium and closely related genera): evolution

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