The Origin of Plasmodium Falciparum from Bonobos

On the Diversity of Malaria Parasites in African Apes and the Origin of Plasmodium falciparum from Bonobos Sabrina Krief1., Ananias A. Escalante2.*, M. Andreina Pacheco2, Lawrence Mugisha3, Claudine Andre´ 4, Michel Halbwax5, Anne Fischer5¤, Jean-Michel Krief6, John M. Kasenene7, Mike Crandfield8, Omar E. Cornejo9, Jean-Marc Chavatte10, Clara Lin11, Franck Letourneur12, Anne Charlotte Gru¨ ner11,12, Thomas F. McCutchan13, Laurent Reńia11,12, Georges Snounou10,11,14,15,16* 1 UMR 7206-USM 104, Eco-Anthropologie et Ethnobiologie, Museúm National d’Histoire Naturelle, Paris, France, 2 School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America, 3 Chimpanzee Sanctuary & Wildlife Conservation Trust (CSWCT), Entebbe, Uganda, 4 Lola Ya Bonobo Bonobo Sanctuary, ‘‘Petites Chutes de la Lukaya’’, Kimwenza–Mont Ngafula, Kinshasa, Democratic Republic of Congo, 5 Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany, 6 Projet pour la Conservation des Grands Singes, Paris, France, 7 Department of Botany, Makerere University, Kampala, Uganda; Makerere University Biological Field Station, Fort Portal, Uganda, 8 Research and Conservation Program, The Maryland Zoo in Baltimore, Baltimore, Maryland, United States of America, 9 Emory University, Program in Population Biology, Ecology, and Evolution, Atlanta, Georgia, United States of America, 10 USM0307, Parasitologie Compareé et Mode`les Expe´rimentaux, Museúm National d’Histoire Naturelle, Paris, France, 11 Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, Singapore, 12 Institut Cochin, Universite´ Paris Descartes, CNRS (UMR 8104), Paris, France; INSERM U567, Paris, France, 13 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Maryland, United States of America, 14 INSERM UMR S 945, Paris, France, 15 Universite´ Pierre & Marie Curie, Faculte´ de Me´decine Pitie´-Salpeˆtrie`re, Paris, France, 16 Department of Microbiology, National University of Singapore, Singapore Abstract The origin of Plasmodium falciparum, the etiological agent of the most dangerous forms of human malaria, remains controversial. Although investigations of homologous parasites in African Apes are crucial to resolve this issue, studies have been restricted to a chimpanzee parasite related to P. falciparum, P. reichenowi, for which a single isolate was available until very recently. Using PCR amplification, we detected Plasmodium parasites in blood samples from 18 of 91 individuals of the genus Pan, including six chimpanzees (three Pan troglodytes troglodytes, three Pan t. schweinfurthii) and twelve bonobos (Pan paniscus). We obtained sequences of the parasites’ mitochondrial genomes and/or from two nuclear genes from 14 samples. In addition to P. reichenowi, three other hitherto unknown lineages were found in the chimpanzees. One is related to P. vivax and two to P. falciparum that are likely to belong to distinct species. In the bonobos we found P. falciparum parasites whose mitochondrial genomes indicated that they were distinct from those present in humans, and another parasite lineage related to P. malariae. Phylogenetic analyses based on this diverse set of Plasmodium parasites in African Apes shed new light on the evolutionary history of P. falciparum. The data suggested that P. falciparum did not originate from P. reichenowi of chimpanzees (Pan troglodytes), but rather evolved in bonobos (Pan paniscus), from which it subsequently colonized humans by a host-switch. Finally, our data and that of others indicated that chimpanzees and bonobos maintain malaria parasites, to which humans are susceptible, a factor of some relevance to the renewed efforts to eradicate malaria. Citation: Krief S, Escalante AA, Pacheco MA, Mugisha L, Andre´ C, et al. (2010) On the Diversity of Malaria Parasites in African Apes and the Origin of Plasmodium falciparum from Bonobos. PLoS Pathog 6(2): e1000765. doi:10.1371/journal.ppat.1000765 Editor: L. David Sibley, Washington University School of Medicine, United States of America Received September 4, 2009; Accepted January 13, 2010; Published February 12, 2010 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This study was financially supported by the Museum National d’Histoire Naturelle (Paris, France), the Fyssen Foundation and a Leakey grant to SK. AAE was supported by an R01 grant (GM080586) from the US National Institutes of Health. The US NIH intramural program supported TFM. LR, ACG, CL and GS were supported by INSERM and the Agency for Science, Technology and Research (A*STAR), Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (AAE); [email protected] or [email protected] (GS) . These authors contributed equally to this work. ¤ Current address: African Insect Science for Food and Health, Nairobi, Kenya Introduction independently colonised hominids [3–6]. The timing of their appearance in Homo sapiens, however, remains unresolved. This is Malaria infections have influenced the development of human of some importance to current efforts to control malaria, because civilizations, and have shaped the genetic make-up of current it will affect how observed patterns of genetic diversity in the human populations. There are four globally distributed Plasmo- parasite populations are interpreted. For example, several dium protozoan parasites that are responsible for malaria in evolutionary genetic approaches rely on reliable phylogenetic humans (P. falciparum, P. vivax, P. malariae and P. ovale). Molecular information to detect putative adaptive genetic variation, thereby phylogenetic analyses have demonstrated that these four identifying genes that might be involved in pathogenesis or in the parasites are not monophyletic [1,2], indicating that they evasion of host immune responses. Addressing these issues is a PLoS Pathogens | www.plospathogens.org 1 February 2010 | Volume 6 | Issue 2 | e1000765 Parasites of Apes and the Origin of Human Malaria Author Summary Results Chimpanzees and gorillas are known to have malaria Blood samples were obtained from 49 chimpanzees, Pan parasites (genus Plasmodium) similar to those that infect troglodytes, in Uganda and the Democratic Republic of the Congo humans. It is likely that detailed molecular studies of these (DRC), and from 42 bonobos, Pan paniscus, in the DRC. Blood parasites will help understand important aspects of the smears were not made available, so the presence and level of malaria disease and of immune defences in humans, and Plasmodium parasites were assessed solely by a highly sensitive PCR could then guide the development of novel control assay, where a small fragment of the small subunit ribosomal RNA measures. However, few studies of parasites in African (ssrRNA) genes is amplified using oligonucleotides that target Apes have been conducted to date. Here we present the sequences conserved in all known Plasmodium species [18]. results of a survey of malaria parasites in chimpanzees and Parasites were detected in 18 animals: 3/3 Pan t. schweinfurthii bonobos, our closest relatives. In chimpanzees, we living wild in Kibale National Park in Uganda, and in 3/8 Pan t. identified two new parasite species closely related to P. troglodytes and 12/42 Pan paniscus cared for in sanctuaries in the falciparum, the most dangerous of the parasites in DRC. Parasitaemias were quite low (,100 parasites per mlof humans. We also found that bonobos harbour malaria blood), consistent with previous observations of naturally infected parasites including P. falciparum. Phylogenetic analyses of apes [13,14]. these parasites strongly suggested that P. falciparum evolved in bonobos, and that it was introduced into We opted to conduct our analyses on the DNA purified directly humans from bonobos at a later date. Overall, our findings from the blood samples, because whole genome amplification have substantially altered our perception of the origin of could lead to artefactual recombination between DNA molecules malaria parasites in humans. from different strains or species of parasites, should any be present in a given sample. Given the low parasite densities in the samples and the limited blood volumes available, efforts were directed at matter of great importance for P. falciparum,theparasite characterizing a small number of genes that have been used in responsible for a substantial proportion of the global malaria recent phylogenetic analyses. Specifically, we targeted the mortality and morbidity [7]. It is now generally accepted that P. mitochondrial genome using oligonucleotide primers that corre- falciparum underwent a population expansion in humans [4,6,8– spond to sequences conserved in Plasmodium. Since we were 11], though how, when and from where humans first acquired P. particularly interested in lineages related to P. falciparum, we used falciparum, is less well established. Suggestions of a host-switch oligonucleotides based on sequences from P. falciparum to target from a

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