Plasmodium simium : a Brazilian focus of anthropozoonotic vivax malaria?
Authors: Matthew J Grigg, Georges Snounou
Journal: The Lancet Global Health (2017)

Around 25 malaria parasite species have been described in non-human primates. By the 1970s, human beings were shown to be susceptible to experimental infection by eight of these, in addition to a naturally acquired infection reported with Plasmodium knowlesi, a parasite of southeast Asian macaques.1Coatney GR Collins WE Warren M Contacos PG The primate malarias. US Government, Washington, DC1971Google Scholar A large focus of zoonotic P knowlesi human infections (historically misdiagnosed as Plasmodium malariae by microscopy) was reported in Malaysia in 2004,2Singh B Kim Sung L Matusop A et al.A large focus of naturally acquired Plasmodium knowlesi infections in human beings.Lancet. 2004; 363: 1017-1024Summary Full Text Full Text PDF PubMed Scopus (775) Google Scholar where it is now the predominant cause of malaria. Cases have subsequently been reported throughout southeast Asia where the natural monkey hosts are distributed.3Moyes CL Shearer FM Huang Z et al.Predicting the geographical distributions of the macaque hosts and mosquito vectors of Plasmodium knowlesi malaria in forested and non-forested areas.Parasit Vectors. 2016; 9: 1-12Crossref PubMed Scopus (68) Google Scholar This discovery was only made possible through molecular diagnosis. The only two parasite species described in South American primates are Plasmodium brasilianum and P simium. P brasilianum is almost morphologically and genetically indistinguishable from P malariae, whereas Plasmodium simium is nearly indistinguishable from Plasmodium vivax. Moreover, human beings have been shown to be susceptible to P brasilianum, and most probably to P simium also.4Deane LM Deane MP Ferreira Neto J Studies on transmission of simian malaria and on a natural infection of man with Plasmodium simium in Brazil.Bull World Health Organ. 1966; 35: 805-808PubMed Google Scholar P brasilianum is found throughout South America, whereas P simium appears restricted to the Atlantic Forest region in southeastern Brazil, with natural hosts including arboreal howler monkeys (Alouatta spp), woolly spider monkeys (Brachyteles arachnoides),5Deane LM Simian malaria in Brazil.Mem Inst Oswaldo Cruz. 1992; 87: 1-20Crossref PubMed Scopus (116) Google Scholar and capuchin monkeys (genera Cebus and Sapajus).6de Alvarenga DAM de Pina-Costa A de Sousa TN et al.Simian malaria in the Brazilian Atlantic forest: first description of natural infection of capuchin monkeys (Cebinae subfamily) by Plasmodium simium.Malar J. 2015; 14: 81Crossref PubMed Scopus (41) Google Scholar The P simium vector, Anopheles (Kerteszia) cruzi, which is also a known human malaria vector, is found almost exclusively in this area, with the ability to feed on both monkeys in the canopy and human beings at ground level.4Deane LM Deane MP Ferreira Neto J Studies on transmission of simian malaria and on a natural infection of man with Plasmodium simium in Brazil.Bull World Health Organ. 1966; 35: 805-808PubMed Google Scholar In The Lancet Global Health, Patrícia Brasil and colleagues7Brasil P Zalis MG de Pina-Costa A et al.Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation.Lancet Glob Health. 2017; (published online August 31.)http://dx.doi.org/10.1016/S2214-109X(17)30333-9PubMed Google Scholar explore whether a relatively recent series of rigorously defined autochthonous cases of malaria from the Atlantic Forest coastal region of Brazil (Rio de Janiero state) arose from a zoonotic focus, given that routine microscopy and standard PCR assays are unable to differentiate between P vivax and P simium, and that malaria in this area was considered to have been eliminated by the late 1970s. Blood samples were taken from 28 human cases and three Alouatta guariba clamitans monkeys and were subjected to amplification of Plasmodium mitochondrial DNA fragments; all were found to contain the two single-nucleotide polymorphisms considered diagnostic for P simium. Three additional human parasite isolates had successful full-length mitochondrial DNA sequencing done, with identical alignment to a P simium reference monkey strain, and specificity verified against a large number of homologous P vivax reference sequences from around the world. Some, if not most, of the autochthonous cases previously diagnosed as P vivax in the Atlantic Forest region are likely to have been P simium acquired via mosquitoes infected from monkeys, thereby making this part of Brazil the site of a second global focus of zoonotic malaria. P simium is thought to ancestrally derive from more than one recent P vivax host switch from human beings to monkeys.8Lim CS Tazi L Ayala FJ Plasmodium vivax: recent world expansion and genetic identity to Plasmodium simium.Proc Natl Acad Sci USA. 2005; 102: 15523-15528Crossref PubMed Scopus (54) Google Scholar It is plausible that the vacant ecological niche in this area increased the vulnerability of a further host switch for P simium back to humans. Contributing factors might include recent human land-use change and encroachment into previously undisturbed enzootic transmission cycles, with subsequent vector or monkey host behavioural adaptation. However, whether zoonotic P simium transmission is an emerging phenomenon or more consistent with long-standing occasional spillover events is not clear. The problem facing Brazil, however, is potentially far more intractable than that posed by P knowlesi in southeast Asia, where human-to-human transmission has yet to be observed. Based on the limited molecular evidence, these infections are more likely to be P vivax behaving as a true anthropozoonosis, with minimal changes since being introduced to South America by the migration of European populations.9Taylor JE Pacheco MA Bacon DJ et al.The evolutionary history of Plasmodium vivax as inferred from mitochondrial genomes: parasite genetic diversity in the Americas.Mol Biol Evol. 2013; 30: 2050-2064Crossref PubMed Scopus (77) Google Scholar Classification of genetically similar Plasmodium species as separate entities is difficult when there is no host specificity. Human infections reported in 2015, denoted as P brasilianum in Venezuela, were found to be genetically identical to P brasilianum in monkeys hosts and P malariae in human beings, and were used to argue (on firmer molecular grounds) for a nomenclatorial revision of P malariae.10Lalremruata A Magris M Vivas-Martínez S et al.Natural infection of Plasmodium brasilianum in humans: man and monkey share quartan malaria parasites in the Venezuelan Amazon.EBIOM. 2015; 2: 1186-1192Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar However, a genuine absence of host preference might require evidence of equally viable onward human-to-human transmission, or human-to-monkey transmission. The epidemiological data presented by Brasil and colleagues7Brasil P Zalis MG de Pina-Costa A et al.Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation.Lancet Glob Health. 2017; (published online August 31.)http://dx.doi.org/10.1016/S2214-109X(17)30333-9PubMed Google Scholar are most consistent with zoonotic-only transmission, including an absence of sequential case-clustering, and predominantly urban-residing older males with a history of recent travel to forest areas. This important study raises a number of remaining questions. Firstly, it becomes imperative to obtain the full genome of P simium to confirm or reject synonymy with P vivax. An anthropozoonotic P vivax reservoir in Brazilian monkeys would pose a substantial threat to malaria elimination throughout the continent and possibly beyond, including potential onwards transmission from hypnozoite relapses. One priority should be to investigate the natural history and biology of these two parasites in their non-human primate hosts. Evaluation of the geographical distribution and prevalence of P simium in both monkey hosts and mosquito vectors will also assist in accurately defining the population at risk. The clinical features and pathogenesis of P simium also remain poorly defined. We declare no competing interests. Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigationThis unequivocal demonstration of zoonotic transmission, 50 years after the only previous report of P simium in people, leads to the possibility that this parasite has always infected people in this region, but that it has been consistently misdiagnosed as P vivax because of an absence of molecular typing techniques. Thorough screening of local non-human primates and mosquitoes (Anopheline) is required to evaluate the extent of this newly recognised zoonotic threat to public health and malaria elimination in Brazil. Full-Text PDF Open Access