The genome of the zoonotic malaria parasite Plasmodium simium reveals adaptations to host switching.

BACKGROUND: Plasmodium simium, a malaria parasite of non-human primates (NHP), was recently shown to cause zoonotic infections in humans in Brazil. We sequenced the P. simium genome to investigate its evolutionary history and to identify any genetic adaptions that may underlie the ability of this parasite to switch between host species. RESULTS: Phylogenetic analyses based on whole genome sequences of P. simium from humans and NHPs reveals that P. simium is monophyletic within the broader diversity of South American Plasmodium vivax, suggesting P. simium first infected NHPs as a result of a host switch of P. vivax from humans. The P. simium isolates show the closest relationship to Mexican P. vivax isolates. Analysis of erythrocyte invasion genes reveals differences between P. vivax and P. simium, including large deletions in the Duffy-binding protein 1 (DBP1) and reticulocyte-binding protein 2a genes of P. simium. Analysis of P. simium isolated from NHPs and humans revealed a deletion of 38 amino acids in DBP1 present in all human-derived isolates, whereas NHP isolates were multi-allelic. CONCLUSIONS: Analysis of the P. simium genome confirmed a close phylogenetic relationship between P. simium and P. vivax, and suggests a very recent American origin for P. simium. The presence of the DBP1 deletion in all human-derived isolates tested suggests that this deletion, in combination with other genetic changes in P. simium, may facilitate the invasion of human red blood cells and may explain, at least in part, the basis of the recent zoonotic infections.

Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation.

BACKGROUND: Malaria was eliminated from southern and southeastern Brazil over 50 years ago. However, an increasing number of autochthonous episodes attributed to Plasmodium vivax have recently been reported from the Atlantic Forest region of Rio de Janeiro state. As the P vivax-like non-human primate malaria parasite species Plasmodium simium is locally enzootic, we performed a molecular epidemiological investigation to determine whether zoonotic malaria transmission is occurring. METHODS: We examined blood samples from patients presenting with signs or symptoms suggestive of malaria as well as from local howler monkeys by microscopy and PCR. Samples were included from individuals if they had a history of travel to or resided in areas within the Rio de Janeiro Atlantic Forest, but not if they had malaria prophylaxis, blood transfusion or tissue or organ transplantation, or had travelled to known malaria endemic areas in the preceding year. Additionally, we developed a molecular assay based on sequencing of the parasite mitochondrial genome to distinguish between P vivax and P simium, and applied this assay to 33 cases from outbreaks that occurred in 2015, and 2016. FINDINGS: A total of 49 autochthonous malaria cases were reported in 2015-16. Most patients were male, with a mean age of 44 years (SD 14·6), and 82% lived in urban areas of Rio de Janeiro state and had visited the Atlantic Forest for leisure or work-related activities. 33 cases were used for mitochondrial DNA sequencing. The assay was successfully performed for 28 samples, and all were shown to be P simium, indicative of zoonotic transmission of this species to human beings in this region. Sequencing of the whole mitochondrial genome of three of these cases showed that P simium is most closely related to P vivax parasites from South America. The malaria outbreaks in this region were caused by P simium, previously considered to be a monkey-specific malaria parasite, related to but distinct from P vivax, and which has never conclusively been shown to infect people before. INTERPRETATION: This 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. FUNDING: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado de Rio de Janeiro, The Brazilian National Council for Scientific and Technological Development (CNPq), JSPS Grant-in-Aid for scientific research, Secretary for Health Surveillance of the Brazilian Ministry of Health, Global Fund, Fundaçao de amparo à pesquisa do estado de Minas Gerais (Fapemig), and PRONEX Program of the CNPq.