A Plethora of Plasmodium Species in Wild Apes: a Source of Human Infection?
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Review Feature review A plethora of Plasmodium species in wild apes: a source of human infection? Julian C. Rayner1, Weimin Liu2, Martine Peeters4, Paul M. Sharp5 and Beatrice H. Hahn2,3 1 Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK 2 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA 3 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA 4 Institut de Recherche pour le De´ veloppement (IRD) and University of Montpellier 1, 34394 Montpellier, France 5 Institute of Evolutionary Biology and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, UK Recent studies of captive and wild-living apes in Africa vivax-like or P. ovale-like by different investigators [10,11]. have uncovered evidence of numerous new Plasmodium Recognizing that P. falciparum and P. reichenowi were species, one of which was identified as the immediate quite distinct from the other known Plasmodium species, it precursor of human Plasmodium falciparum. These find- was suggested more than 50 years ago that the former ings raise the question whether wild apes could be a should be placed in a separate genus, Laverania [12]. recurrent source of Plasmodium infections in humans. Although this taxonomy was not widely adopted, the term This question is not new, but was the subject of intense has recently been resurrected and is useful as a subgenus investigation by researchers in the first half of the last designation [13]. century. Re-examination of their work in the context of Surprisingly, genetic material was obtained for only one recent molecular findings provides a new framework of these three Plasmodium species found in apes. In 1968, a to understand the diversity of Plasmodium species chimpanzee that had been imported into the USA was and to assess the risk of future cross-species transmis- found to be infected with P. reichenowi. The parasite sions to humans in the context of proposed malaria was isolated at the Centers for Disease Control (CDC) eradication programs. and subsequently propagated for molecular and biological analyses [14]. This P. reichenowi isolate has been used for Ape Plasmodium infections: a historical perspective numerous comparative genetic studies [15–18], ranging Plasmodium parasites are extraordinarily successful and from single-gene to whole-genome analyses, for example, infect many vertebrate hosts, ranging from reptiles to birds to identify genes in P. falciparum that are under differen- to mammals. Our closest relatives, the African great apes, tial selection pressures [19]. A full-length genome sequence are no exception. While working in Cameroon in 1917, is now nearing completion (M. Berriman, personal com- Eduard Reichenow observed three morphologically dis- munication). Although P. schwetzi was also isolated by the tinct Plasmodium parasites in the blood of chimpanzees CDC [11,20], no aliquots of this isolate apparently remain, (Pan troglodytes) and gorillas (Gorilla gorilla) [1], a finding and no DNA was ever recovered from this specimen (J.W. soon confirmed by Saul Adler and Donald Blacklock in Barnwell, personal communication). P. rhodaini was never Sierra Leone [2,3]. In the following decades, Plasmodium genetically characterized. parasites in gorillas and chimpanzees were studied at several sites across west and central Africa [4–9]. The A molecular revolution: ape parasites revisited consensus reached from this work was that there were This view of the three species of Plasmodium in apes from indeed three Plasmodium species infecting African great west and central Africa (P. reichenowi, P. schwetzi and P. apes, and that these were distinguishable based on their rhodaini), which mirror the three human Plasmodium life-cycle and morphology. One species bore a striking species (P. falciparum, P. ovale and P. malariae) found resemblance to human P. falciparum, so much so that it in the same regions, has been completely revised in the was initially assumed to be the same species; only later was past two years. The first suspicion that the old descriptors it accepted to be distinct, and named P. reichenowi [9].A might not be sufficient came from the identification of second parasite in apes, P. rhodaini, closely resembled P. parasites morphologically resembling P. falciparum in malariae found in humans, whereas the third, P. schwetzi, two pet chimpanzees from Gabon [21]. When the complete was more difficult to characterize and was referred to as P. mitochondrial genome of one of these parasites was se- quenced, it became clear that it was related to, but quite Corresponding author: Rayner, J.C. ([email protected]) divergent from, P. falciparum and the CDC isolate of 222 1471-4922/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2011.01.006 Trends in Parasitology, May 2011, Vol. 27, No. 5 Review Trends in Parasitology May 2011, Vol. 27, No. 5 Box 1. Approaches to studying Plasmodium infection in was intriguing: sequences from three of these lineages apes were found only in chimpanzee samples, whereas sequences from the other three clades were found only All African apes are highly endangered, thus precluding invasive studies of wild populations. Given this, options to study ape in samples from western gorillas (G. gorilla), even when Plasmodium infections are limited. One strategy is to partner with both of these host species were sampled at the same ape sanctuaries and analyze specimens collected for diagnostic geographical location. In contrast, Plasmodium sequences purposes as part of routine health measures. The advantage of this were not detected in eastern gorillas (G. beringei) or bono- approach is access to blood samples, which may yield parasite bos (P. paniscus) despite several hundred samples being isolates as well as Plasmodium sequences. The disadvantage is that sanctuary apes live in close proximity to humans and may thus be tested [25]. The samples taken from eastern gorillas were exposed to, and possibly infected by, human parasites. The other collected at sites no more than 500–700 m above sea level. strategy is to screen ape fecal samples collected from the forest Hence, the absence of Laverania parasites was not simply a floor (Figure I) or, in the case of habituated communities, tissue function of high altitude. samples from apes that are found dead, for Plasmodium infections [22,30]. The advantage of this approach is that much larger numbers of apes can be studied, and that all individuals are sampled within A minimum of six ape Laverania species their natural habitat. The disadvantage is that parasite loads may be Naming these various Laverania clades as different Plas- [()TD$FIG]much lower than in blood samples, and that morphological modium species on the basis of genetic information alone is characterization of parasites is not possible. likely to be controversial, but seems necessary at this time. The endangered status of African apes will make it difficult to obtain infected blood to derive Plasmodium isolates. Moreover, the high frequency of mixed-species infections (see below) will confound meaningful correlations of para- site morphology with genetic information from the same sample. Thus, it is unclear if and when the morphological and biological data traditionally used for the taxonomic description of new Plasmodium species will become avail- able. However, there is a pressing need for a standardized nomenclature to provide a common framework for future research because there is confusion surrounding recently TRENDS in Parasitology proposed species names. We believe that a strong case can Figure I. Non-invasive testing of ape Plasmodium infections. An ape fecal be made that the six clades of ape Plasmodium sequences sample is collected at a remote forest site by an experienced tracker and reflect distinct parasite species. Nevertheless, we recog- preserved for shipment and storage in RNAlater (Ambion). nize that the proposal described below will remain tenta- tive until a full taxonomic evaluation has been completed. P. reichenowi. This led to the proposal of a new species, P. Several lines of evidence indicate that the six lineages gaboni. Four additional studies rapidly followed that also within Laverania each represent a distinct species. First, reported sequences from P. falciparum-like parasites in the various mtDNA clades are at least as divergent from African apes [13,22–24]. All of these pointed to the exis- each other as are P. falciparum and P. reichenowi [25], tence of additional species within the Laverania subgenus which in turn are much more divergent than the two [13,21–24], but their precise number and true host associa- recently proposed species within P. ovale [26]. Second, tions were unclear. For example, various chimpanzee-de- as noted above, the clades exhibit remarkably strict host rived lineages were all placed in one species [22], or split specificity, indicating isolation at least between the para- into four species [13,24]. In addition, only relatively few sites infecting chimpanzees and gorillas. Third, both of samples were analyzed, most of which were derived from these aspects of the mtDNA phylogeny are recapitulated sanctuary apes that could have become infected in captivi- by sequences from the two other parasite genomes, i.e. the ty. Finally, some of the new sequences were clearly poly- clpC gene from apicoplast DNA and the ldh gene from the merase chain reaction (PCR)-induced hybrids which nuclear genome, despite the fact that fewer clpC and ldh formed lineages intermediate between clades [23]. sequences were analyzed [25]. The apicoplast genome These uncertainties have since been resolved by a large- appears to be uniparentally inherited in the same fashion scale molecular epidemiological study [25] that used non- as mtDNA [27–29]. However, biparentally inherited nucle- invasive methods (Box 1) to examine nearly 3,000 fecal ar genes can assort independently of the organelle gen- samples from wild-living apes at multiple sites across omes and so the ldh data in particular indicate that the Africa (Figure 1).