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

Abstract

Oxford, Headington, Oxford, OX3 9DU, UK 41 42 §) Contributed equally, arranged alphabetically 43 †) Corresponding authors 44 45 46 Summary 47 48 Plasmodium simium, a malaria parasite of non-human primates in the Atlantic forest region of 49Brazil was recently shown to cause zoonotic infection in humans in the region. Phylogenetic 50 analyses based on the whole genome sequences of six P. simium isolates infecting humans 51 and two isolates from brown howler monkeys revealed that P. simium is monophyletic within 52 the broader diversity of South American Plasmodium vivax, consistent with the hypothesis 53 that P. simium first infected non-human primates as a result of a host-switch from humans 54 carrying P. vivax. We provide molecular evidence that the current zoonotic infections of 55 people have likely resulted from multiple independent host switches, each seeded from a 56 different monkey infection. Very low levels of genetic diversity within P. simium genomes 57 and the absence of P. simium-P. vivax hybrids suggest that the P. simium population emerged 58 recently and has subsequently experienced a period of independent evolution in Platyrrhini 59 monkeys. We further find that Plasmodium Interspersed Repeat (PIR) genes, Plasmodium 60Helical Interspersed Subtelomeric (PHIST) genes and Tryptophan-Rich Antigens (TRAg) 61 genes in P. siumium are genetically divergent from P. vivax and are enriched for non-62 synonymous single nucleotide polymorphisms, consistent with the rapid evolution of these 63 genes. Analysis of genes involved in erythrocyte invasion revealed several notable differences 64 between P. vivax and P. simium, including large deletions within the coding region of the 65 Duffy Binding Protein 1 (DBP1) and Reticulocyte Binding Protein 2a (RBP2a) genes in P. 66 simium. Genotyping of P. simium isolates from non-human primates (NHPs) and zoonotic 67 human infections showed that a precise deletion of 38 amino acids in DBP1 is exclusively 67 present in all human infecting isolates, whereas non-human primate infecting isolates were 68 polymorphic for the deletion. We speculate that these deletions in the parasite-encoded key 69 erythrocyte invasion ligands and the additional rapid genetic changes have facilitated zoonotic 70 transfer to humans. Non-human primate malaria parasites can be considered a reservoir of 71 potential infectious human parasites that must be considered in any attempt of malaria 72 elimination. The genome of P. simium will thus form an important basis for future functional 73 characterizations on the mechanisms underlying malaria zoonosis. 74 75 76 Introduction 77 78 There are currently eight species of malaria parasites known to cause disease in humans; 79 Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale 80 curtisi, Plasmodium ovale wallikeri, Plasmodium knowlesi, Plasmodium cynomolgi and 81 Plasmodium simium. The latter three species are more commonly parasitic on non-human 82 primates and have only relatively recently been shown to infect humans 1-3 . ...

A mathematical model for zoonotic transmission of malaria in the Atlantic Forest: exploring the effects of variations in vector abundance and acrodendrophily

“…brasilianum is identical to P. malariae, and P. simium to P. vivax [8]. This similarity has been confirmed by molecular studies, which showed a high identity between the genomes in each of these pairs of plasmodia [12][13][14][15], suggesting recent speciation and reinforcing the possibility of Plasmodium transmission from monkeys to humans and vice versa [15][16][17].…”

“…Howler monkeys (Alouatta clamitans) are probably the main reservoir of malarial parasites (P. simium / P. vivax) that cause zoonotic infections in humans in the Atlantic Forest [11]. Analysis of the P. simium genome revealed that these zoonotic parasites underwent host-switching adaptations, including switching (1) from European humans carrying P. vivax to New World monkeys during the first centuries of Brazilian colonization and (2) from New World monkeys carrying P. simium (a descendent form of P. vivax) to modern humans engaging in forest activities [15].…”

Atlantic Forest Malaria: A Review of More than 20 Years of Epidemiological Investigation

“…Interestingly, the same study also reported significant differences between P. vivax and P. simium in the genes encoding region 1 of the Duffy binding protein 1 (DBP1) and the reticulocyte binding protein 2 (RBP2a). The authors suggest that these changes in the key encoding erythrocyte invasion ligands together with other genetic changes possibly facilitated the transfer of P. simium to humans [ 44 ].…”

Alternative Invasion Mechanisms and Host Immune Response to Plasmodium vivax Malaria: Trends and Future Directions

“…A majority of transcription take place during the schizont-ring transition [ 121 ], suggesting their role in erythrocyte invasion. The proportion of non-synonymous SNPs in PvTRAg genes was shown to be significantly high, suggesting the effect of diversifying selection related to antigenic function [ 122 ]. Nine PvTRAgs have been shown to bind to human erythrocytes, including PvTRAg33.5, PvTRAg35.2, PvTRAg69.4, PvTRAg34, PvTRAg38, PvTRAg36, PvTRAg74, PvTRAg26.3, and PvTRAg36.6.…”