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Plasmodium knowlesi is a zoonotic malaria parasite that has gained increasing medical interest over the past two decades. This zoonotic parasitic infection is prevalent in Southeast Asia and causes many cases with fulminant pathology. Despite several biogeographical restrictions that limit its distribution, knowlesi malaria cases have been reported in different parts of the world due to travelling and tourism activities. Here, breakthroughs and key information generated from recent (over the past five years, but not limited to) studies conducted on P. knowlesi were reviewed, and the knowledge gap in various research aspects that need to be filled was discussed. Besides, challenges and strategies required to control and eradicate human malaria with this emerging and potentially fatal zoonosis were described.

Of the 5 human malarial parasites, Plasmodium falciparum and Plasmodium vivax are the most prevalent species globally, while Plasmodium malariae, Plasmodium ovale curtisi and Plasmodium ovale wallikeri are less prevalent and typically occur as mixed-infections. Plasmodium knowlesi, previously considered a non-human primate (NHP) infecting species, is now a cause of human malaria in Malaysia. The other NHP Plasmodium species, Plasmodium cynomolgi, Plasmodium brasilianum, Plasmodium inui, Plasmodium simium, Plasmodium coatneyi and Plasmodium fieldi cause malaria in primates, which are mainly reported in southeast Asia and South America. The non-knowlesi NHP Plasmodium species also emerged and were found to cross-transmit from their natural hosts (NHP) – to human hosts in natural settings. Here we have reviewed and collated data from the literature on the NHPs-to-human-transmitting non-knowlesi Plasmodium species. It was observed that the natural transmission of these NHP parasites to humans had been reported from 2010 onwards. This study shows that: (1) the majority of the non-knowlesi NHP Plasmodium mixed species infecting human cases were from Yala province of Thailand; (2) mono/mixed P. cynomolgi infections with other human-infecting Plasmodium species were prevalent in Malaysia and Thailand and (3) P. brasilianum and P. simium were found in Central and South America.

The global malaria burden sometimes obscures that the genus Plasmodium comprises diverse clades with lineages that independently gave origin to the extant human parasites. Indeed, the differences between the human malaria parasites were highlighted in the classical taxonomy by dividing them into two subgenera, the subgenus Plasmodium , which included all the human parasites but Plasmodium falciparum that was placed in its separate subgenus, Laverania . Here, the evolution of Plasmodium in primates will be discussed in terms of their species diversity and some of their distinct phenotypes, putative molecular adaptations, and host–parasite biocenosis. Thus, in addition to a current phylogeny using genome-level data, some specific molecular features will be discussed as examples of how these parasites have diverged. The two subgenera of malaria parasites found in primates, Plasmodium and Laverania , reflect extant monophyletic groups that originated in Africa. However, the subgenus Plasmodium involves species in Southeast Asia that were likely the result of adaptive radiation. Such events led to the Plasmodium vivax lineage. Although the Laverania species, including P. falciparum , has been considered to share “avian characteristics,” molecular traits that were likely in the common ancestor of primate and avian parasites are sometimes kept in the Plasmodium subgenus while being lost in Laverania . Assessing how molecular traits in the primate malaria clades originated is a fundamental science problem that will likely provide new targets for interventions. However, given that the genus Plasmodium is paraphyletic (some descendant groups are in other genera), understanding the evolution of malaria parasites will benefit from studying “non- Plasmodium ” Haemosporida.

Zoonotic Plasmodium infections in humans in many Southeast Asian countries have been increasing, including in countries approaching elimination of human-only malaria transmission. Most simian malarias in humans are caused by Plasmodium knowlesi , but recent research shows that humans are at risk of many different simian Plasmodium species. In Southeast Asia, simian Plasmodium species are mainly transmitted by mosquitoes in the Anopheles leucosphyrus and Anopheles dirus complexes. Although there is some evidence of species outside the Leucosphyrus Group transmitting simian Plasmodium species, these await confirmation of transmission to humans. The vectors of monkey malarias are mostly found in forests and forest fringes, where they readily bite long-tailed and pig-tailed macaques (the natural reservoir hosts) and humans. How changing land-uses influence zoonotic malaria vectors is still poorly understood. Fragmentation of forests from logging, agriculture and other human activities is associated with increased zoonotic Plasmodium vector exposure. This is thought to occur through altered macaque and mosquito distributions and behaviours, and importantly, increased proximity of humans, macaques, and mosquito vectors. Underlying the increase in vector densities is the issue that the land-use change and human activities create more oviposition sites and, in correlation, increases availably of human blood hosts. The current understanding of zoonotic malaria vector species is largely based on a small number of studies in geographically restricted areas. What is known about the vectors is limited: the data is strongest for distribution and density with only weak evidence for a limited number of species in the Leucosphyrus Group for resting habits, insecticide resistance, blood feeding habits and larval habitats. More data are needed on vector diversity and bionomics in additional geographic areas to understand both the impacts on transmission of anthropogenic land-use change and how this significant disease in humans might be controlled.

During the twentieth century, there was an explosion in understanding of the malaria parasites infecting humans and wild primates. This was built on three main data sources: from detailed descriptive morphology, from observational histories of induced infections in captive primates, syphilis patients, prison inmates and volunteers, and from clinical and epidemiological studies in the field. All three were wholly dependent on parasitological information from blood-film microscopy, and The Primate Malarias” by Coatney and colleagues (1971) provides an overview of this knowledge available at that time. Here, 50 years on, a perspective from the third decade of the twenty-first century is presented on two pairs of primate malaria parasite species. Included is a near-exhaustive summary of the recent and current geographical distribution for each of these four species, and of the underlying molecular and genomic evidence for each. The important role of host transitions in the radiation of Plasmodium spp. is discussed, as are any implications for the desired elimination of all malaria species in human populations. Two important questions are posed, requiring further work on these often ignored taxa. Is Plasmodium brasilianum, circulating among wild simian hosts in the Americas, a distinct species from Plasmodium malariae ? Can new insights into the genomic differences between Plasmodium ovale curtisi and Plasmodium ovale wallikeri be linked to any important differences in parasite morphology, cell biology or clinical and epidemiological features?

Parasites regularly switch into new host species, representing a disease burden and conservation risk to the hosts. The distribution of these parasites also gives insight into characteristics of ecological networks and genetic mechanisms of host-parasite interactions. Some parasites are shared across many species, whereas others tend to be restricted to hosts from a single species. Understanding the mechanisms producing this distribution of host specificity can enable more effective interventions and potentially identify genetic targets for vaccines or therapies. As ecological connections between human and local animal populations increase, the risk to human and wildlife health from novel parasites also increases. Which of these parasites will fizzle out and which have the potential to become widespread in humans? We consider the case of primate malarias, caused by Plasmodium parasites, to investigate the interacting ecological and evolutionary mechanisms that put human and nonhuman primates at risk for infection. Plasmodium host switching from nonhuman primates to humans led to ancient introductions of the most common malaria-causing agents in humans today, and new parasite switching is a growing threat, especially in Asia and South America. Based on a wild host- Plasmodium occurrence database, we highlight geographic areas of concern and potential areas to target further sampling. We also discuss methodological developments that will facilitate clinical and field-based interventions to improve human and wildlife health based on this eco-evolutionary perspective.

Macaques are important reservoirs of zoonotic malaria in Southeast Asia. Although cross-sectional malaria surveys have been conducted in macaques, little is known about intra-host infection dynamics and host variation in susceptibility to infection in these infectious reservoirs. We performed a longitudinal monitoring of Plasmodium and Hepatocystis infections by microscopy, species-specific polymerase chain reaction (PCR) and targeted amplicon deep sequencing (TADS) in three long-tailed macaques and 20 pig-tailed macaques in two districts of Narathiwat Province, southern Thailand. In total, 104 macaques’ blood samples were obtained during 5 visits with sequential time intervals of 9, 4, 7 and 12 months. Transiently patent Plasmodium infections with low parasite density ( ≤ 1,050 parasites/µL) occurred in 7 pig-tailed macaques, while PCR and TADS diagnosed infections in 45 (43.27%) blood samples with one or more species of parasites, including Plasmodium knowlesi , P. cynomolgi , P. inui , P. fieldi , P. coatneyi , P. aff. coatneyi and Hepatocystis sp. in one long-tailed and 12 pig-tailed macaques. Compared with PCR, TADS additionally detected co-infecting species in 22 of 45 ( 48.89%) samples. Although living in close proximity to other infected macaques, seven macaques were free from infection during the 32-month period. Infections for 4 to 32 months with malaria parasites carrying identical complete mitochondrial genome sequences were reaffirmed in 10 macaques. Potentially new infections were detected transiently or over a long period during the course of the infections while competitive exclusion seemed to occur between Hepatocystis sp. and Plasmodium taxa. Macaques’ Duffy phenotypes did not influence differential susceptibility to Plasmodium infections. These results suggest the ecological complexity of hemoparasite infections in natural reservoirs of zoonotic malaria. The long period of Plasmodium infections in macaques could affect the transmission and control of the disease.

Malaria is a vector-borne disease caused by protozoan parasites of the genus Plasmodium . Plasmodium vivax is the most prevalent human-infecting species in the Americas. However, the origins of this parasite in this continent are still debated. Similarly, it is now accepted that the existence of Plasmodium simium is explained by a P. vivax transfer from humans to monkey in America. However, many uncertainties still exist concerning the origin of the transfer and whether several transfers occurred. In this review, the most recent studies that addressed these questions using genetic and genomic approaches are presented.

This study presents the complete mitochondrial genome sequence of Plasmodium pitheci , a malaria parasite that infects Bornean orang-utans ( Pongo pygmaeus ). The mitochondrial genome spans 5871 bp in length encoding all essential mitochondrial genes in a conserved arrangement typical of Plasmodium species. Using Bayesian phylogenetic analyses, the evolutionary relationships of P. pitheci with other Plasmodium species that infect non-human primates were investigated. Findings of this study confirm that the previously identified Plasmodium sp. VM and VS and Plasmodium sp. Pongo clade A and clade B from orang-utans correspond to P. pitheci. However, the taxonomic classification of Plasmodium sp. Pongo clade C remains unresolved. The detection of P. pitheci infections in orang-utans across Borneo provides insights into the parasite’s geographic distribution. This genomic information contributes to a deeper understanding of P. pitheci and its evolutionary relationship with other malaria parasites. Comparative genomics with other Plasmodium species, including those infecting humans, will deepen the general understanding of malaria's evolutionary pathways. Furthermore, the availability of the complete mitochondrial genome of this parasite provides a foundation for developing species-specific molecular diagnostic tools. These tools will improve malaria diagnosis in orang-utans, assist in conservation efforts, and potentially aid in zoonotic malaria control strategies for humans in regions where cross-species transmission is a concern.

Background The recent deforestation for agricultural, mining, and human re-settlement has significantly reduced the habitat of many non-human primates (NHPs) in Indonesia and intensifies interaction between the NHPs and humans and thus opening the possibility of pathogen spill-over. The emergence of zoonotic malaria, such as Plasmodium knowlesi , poses an immense threat to the current malaria control and elimination that aims for the global elimination of malaria by 2030. As malaria in humans and NHPs is transmitted by the female Anopheles mosquito, malaria vector control is very important to mitigate the spill-over of the malaria parasite to humans. The present study aims to explore the Anopheles species diversity in human settlements adjacent to the wildlife sanctuary forest in Buton Utara Regency, Southeast Sulawesi, Indonesia, and identify the species that potentially transmit the pathogen from monkey to human in the area. Methods Mosquito surveillance was conducted using larval and adult collection, and the collected mosquitoes were identified morphologically and molecularly using the barcoding markers, cytochrome oxidase subunit I (COI), and internal transcribed species 2 (ITS2) genes. Plasmodium sporozoite carriage was conducted on mosquitoes collected through human landing catch (HLC) and human-baited double net trap (HDNT). Results The results revealed several Anopheles species, such as Anopheles flavirostris (16.6%), Anopheles sulawesi (3.3%), Anopheles maculatus (3.3%), Anopheles koliensis (1.2%), and Anopheles vagus (0.4%). Molecular analysis of the sporozoite carriage using the primate-specific malaria primers identified An. sulawesi , a member of the Leucosphyrus group, carrying Plasmodium inui sporozoite. Conclusions This study indicates that the transmission of zoonotic malaria in the area is possible and alerts to the need for mitigation efforts through a locally-tailored vector control intervention and NHPs habitat conservation.