Unresolved direction of host transfer of Plasmodium vivax v. P. simium and P. malariae v. P. brasilianum
Introduction
Malaria represents a severe problem of public health worldwide, with approximately 350–500 million clinical cases and 1–3 million deaths annually (Breman et al., 2004, Nahlen et al., 2005). Among the four species of malaria parasite that infect humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale), P. vivax is the most geographically widespread. It accounts for 70–80 million clinical cases annually, across much of tropical and subtropical Asia, Central and South America, the Middle East, and Africa (Mendis et al., 2001). P. falciparum is the most malignant species, as it accounts for 80% of human malaria's morbidity and mortality, mostly in sub-Saharan Africa.
Determining the evolutionary history of Plasmodium parasites and their hosts holds a great biological relevance for understanding the pathogenicity and life-history traits of primate malarias (Martinsen et al., 2008, Rich et al., 2009). To date, molecular phylogenetic studies have mainly focused on the origin of P. falciparum and its relationships to other human and animal malaria parasite species (Waters et al., 1991, Escalante and Ayala, 1994, Escalante et al., 1995, Escalante et al., 1998, Escalante et al., 2004, Joy et al., 2003, Rich and Ayala, 2003, Jeffares et al., 2007). Until recently, there has not been general agreement about the origin and age of the extant populations of P. falciparum (Rich and Ayala, 2000, Volkman et al., 2001, Mu et al., 2002, Joy et al., 2003, Hartl, 2004, Escalante et al., 2005, Hagner et al., 2007, Jeffares et al., 2007). Indeed, the origin of P. falciparum still remains controversial. However, four recent papers (Rich et al., 2009, Prugnolle et al., 2010, Krief et al., 2010, Duval et al., 2010) indicate that P. falciparum originated from parasites of African great apes, most likely from P. reichenowi, a common chimpanzee parasite.
Much less is known about the evolutionary history of P. vivax, perhaps in part because its lesser virulence has not stimulated as much research as for P. falciparum, but also because it is difficult to maintain this parasite under in vitro continuous culture conditions (Golenda et al., 1997). Phylogenetic analyses have placed P. vivax among the Asian primate malarias (Escalante et al., 1995, Escalante et al., 2005, Mu et al., 2005, Cornejo and Escalante, 2006). Nevertheless, the high prevalence of Duffy negativity (absence of the Duffy blood-group antigen, which protects against vivax malaria infection) among human populations in sub-Saharan Africa has been interpreted as evidence favoring the African origin of P. vivax (Livingstone, 1984, Carter and Mendis, 2002, Carter, 2003).
Recent studies have shown a paucity of synonymous sites in P. vivax, which may suggest that the world expansion of human vivax malaria is of recent origin (<10,000 years ago) (Cui et al., 2003, Feng et al., 2003, Leclerc et al., 2004, Lim et al., 2005). A study, based on polymorphisms in two nuclear genes and one plastid gene, suggests that the extant populations of P. vivax originated 45–82 Kya (Escalante et al., 2005). The discovery of near genetic identity between P. vivax and P. simium, a platyrrhine monkey parasite, raises the possibility that a host transfer has occurred between humans and New World monkeys in very recent evolutionary times (Escalante and Ayala, 1994, Ayala et al., 1999, Leclerc et al., 2004, Escalante et al., 2005). Moreover, a study based on polymorphisms in the Csp (circumsporozoite protein) gene has shown that at least two host transfers have occurred between humans and New World monkeys, with alternative reasons given that favor one or the other of the two possible directions of host transfer (Lim et al., 2005).
Questions about the origin and the evolutionary history of another human malaria parasite, P. malariae, also remain largely unresolved, partly because it is not as predominant as it may once have been and, thus, it has failed to stimulate as much research as P. falciparum or even P. vivax. P. malariae is genetically indistinguishable from P. brasilianum, a parasite infecting New World monkeys in Central and South America, which again suggests a recent host transfer between humans and primates (Escalante et al., 1995, Escalante et al., 1998, Qari et al., 1996). The direction of the transfer remains also unsettled, with available reasons favoring one or the other of the two possible directions of host transfer, New World monkeys to humans or vice versa (Ayala et al., 1998).
Our study combines, for the first time, the analysis of sequences available in GenBank for four different genes, three protein-coding genes: Csp (circumsporozoite protein), Cytb (cytochrome b), Msp-1 (merozoite surface protein-1), as well as the SSU rRNA gene. These sequences have not previously been analyzed together. In contrast to previous works, our study investigates the evolutionary and phylogenetic relationships, not only between P. vivax and P. simium, but also between P. malariae and P. brasilianum. Studies focusing on this last pair of species still remain limited, if not inexistent. In our study, we did not intend to show that P. vivax and P. simium are close relatives and that P. malariae and P. brasilianum are also close relatives. Those facts have been already documented in previous studies. Our work aimed to compare the evolutionary history between these two pairs of species and to determine if the host transfers in those species occurred from humans to New World monkeys. The originality of our work also relies on the unique combination of the analytical approaches used, which would allow us to predict the direction of transfer of these pathogens between humans and New World monkeys. According to data generated from previous studies, we expect a scarcity of synonymous substitutions in both human malarial species. A recent origin of both human parasites is therefore expected, with a possible scenario that host transfers occurred from humans to monkeys after the colonization of the Americas. Our results support a recent transfer in both cases, although we cannot settle with certainty the direction of the host transfer, owing particularly to the limited availability of strains of the two primate malarias, P. simium and P. brasilianum. Our PAML analysis also indicated the lack of sites under diversifying selection for the genes studied, with the exception of the Csp gene in P. vivax and P. simium. This finding is consistent with the recent origin of one of these two parasite species. Moreover, no positively selected site was identified in the Csp and Msp-1 genes in P. malariae and P. brasilianum. This result suggests that P. malariae and P. brasilianum may have diverged even more recently than P. vivax and P. simium. In any case, the scarcity of neutral polymorphisms suggests that both, P. vivax and P. malariae, are recent human parasites or, alternatively, that they have experienced recent population bottlenecks.
Section snippets
DNA sequences
Table 1 lists the geographic origin of the malaria strains and their accession numbers for the coding sequences of the Csp, Cytb and Msp-1 genes, as well as the SSU rRNA gene sequences. The genes of P. vivax, P. malariae, P. simium, and P. brasilianum are from isolates collected from global malarial endemic regions. The number of sequences varies greatly among species and genes, with fairly numerous strains of P. vivax Csp (24 sequences), Cytb (32 sequences), and SSU rRNA (8 sequences); but
Results
Fig. 1 displays the phylogenetic relationships among the P. vivax and P. simium strains for each of the three genes studied in these two species (Csp, Cytb, and SSU rRNA). Fig. 2 shows the phylogenies derived from the Csp, Msp-1, and SSU rRNA genes among the P. malariae and P. brasilianum strains. The outgroups yield similar phylogenetic trees for all the genes analyzed, confirming indeed the stability of the topology of these trees. Notice, however, the position of one P. simium strain (U69605
Discussion
The circumsporozoite protein (CSP) has been extensively studied in human Plasmodium parasites because of its immune significance as the major surface protein of the sporozoites. The Plasmodium Csp gene, which encodes CSP, consists of a 5′-NR terminal region, a central region of tandem repeats, and a 3′-NR terminal region. Based on an analysis of 492 bp from the two terminal regions, Escalante et al. (1995) showed that the human parasite P. vivax is genetically indistinguishable from the New
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