Plasmodium malariae Malaria: From Monkey to Man?

Abstract

Parasites are engaged in an eternal arms race with their hosts, with both sides continually reacting and adapting to try to either maintain or eliminate infection. One outcome of this coevolutionary struggle can be host species-specificity, where continued cycles of adaptation essentially isolate a parasite within a given host, preventing it from infecting even closely related species. Plasmodium parasites, the causative agents of malaria, are no exception. The most extreme examples are perhaps Plasmodium falciparum, which causes most human malaria mortality, and the cluster of ape parasites from which it emerged. Within this subgenus there appears to be remarkably tight host species specificity, with some Laverania species infecting chimpanzees and others gorillas, even when the two are sympatric (Liu et al., 2010). What isolates Plasmodium parasites within these closely related primates is not known, although host-parasite protein–protein interactions involved in cellular recognition may provide part of the answer (Wanaguru et al., 2013). Not all Plasmodium parasites are so isolated however. Plasmodium knowlesi is perhaps the most widely known example, which primarily infects rhesus macaques but is also the cause of thousands of zoonotic infections in humans (Singh et al., 2004). Plasmodium malariae, one of the four predominant causes of human malaria, is a case where the species-specificity, or lack thereof, has been frequently disputed. P. malariae was almost certainly the first malaria parasite ever observed by Charles Laveran, who won the Nobel Prize for discovering the cause of malaria (Coatney et al., 1971). Found throughout the tropical world from Africa to South America, P. malariae remains the most understudied and mysterious human malaria parasite because it causes few complications and is frequently undiagnosed. The question of the origin of P. malariae remains disputed, in large part because of the existence of two morphologically very similar, perhaps identical, species — Plasmodium rhodaini in African apes, and Plasmodium brasilianum in New World monkeys in South America (Coatney et al., 1971). Cross-species infections shows that both can be forced to cross host barriers experimentally, and P. brasilianum is now commonly thought to be an anthroponosis from P. malariae parasites first introduced to South America from Africa during European occupation and colonization, although others have argued that transmission originally occurred in the opposite direction (Coatney et al., 1971; Tazi & Ayala, 2011). Lalremruata et al. now establish for the first time that cross-species transmission of P. brasilianum can happen naturally from monkey to man (Lalremruata et al., 2015). Surveying remote indigenous communities in the Venezuelan Amazon, they identified human Plasmodium infections that were defined as P. malariae based on established species-specific diagnostics, but were 100% identical in sequence, at least at the loci investigated, to previously published P. brasilianum sequences from South American monkeys. The inference is clear — individuals in these communities are infected with what would be called P. brasilianum if they were isolated from monkeys rather than humans. Phylogenetic analyses incorporating other existing P. malariae and P. brasilianum sequences identified a single monphyletic clade, with no mutations differentiating them. Lalremruata et al., argue that in South America P. malariae and P. brasilianum can be considered a single anthropozoonotic species, circulating freely between monkeys and humans (Lalremruata et al., 2015). Is it time therefore to retire the name P. brasilianum (and perhaps also P. rhodaini in Africa), and identify P. malariae as the most broadly adapted and successful Plasmodium parasite identified to date, capable of infecting a wide range of primate species? Not quite. Lalremruata et al. used a unique sample set from some of the most isolated human communities on the planet, but were limited by the number of loci that they could investigate because so few P. malariae and P. brasilianum samples have been studied genetically. No reference genome for P. malariae currently exists, in large part because of the generally low parasite density found in most P. malariae infections, which results in limited DNA yield. While next-generation sequencing technologies have revolutionised the amount of material needed to generate whole genome sequence from many Plasmodium species, creating a high quality reference genome from scratch still requires a good quantity of DNA, and preferably requires using multiple sequencing technologies. Once such a reference exists, future studies can amplify and sequence multiple loci from both P. malariae and P. brasilianum. Even better would be a comprehensive study comparing genomes from both P. malariae and P. brasilianum from multiple sites across South America, which would finally and definitively establish whether they are the same or distinct species. Why does all this matter? As the scientific community pushes towards malaria elimination, the question of which Plasmodium species have non-human hosts that could serve as a reservoir for continual infections becomes a critical one. For P. malariae, the issue of zoonotic infections may be a very difficult problem indeed.