Humans, macaques, and malaria parasites in a shared and changing landscape
Authors: Daniel M Parker
Journal: The Lancet Planetary Health (2019)

Plasmodium knowlesi, a simian malaria that naturally infects long-tailed macaques (Macaca fascicularis) and pig-tailed macaques (Macaca nemestrina), was discovered in a long-tailed macaque from Singapore in 1931.1Knowles R Gupta BMD A Study of monkey-malaria, and its experimental transmission to man.Ind Med Gaz. 1932; 67: 301-320PubMed Google Scholar Although simian malarias were known to be capable of experimentally infecting humans, questions remained about their zoonotic potential. The first known natural infection of a human by a simian malaria was documented in 1965, when a surveyor for the US Army Map Service, working deep in the jungles of peninsular Malaysia, was infected by P knowlesi.2Chin W Contacos PG Coatney GR Kimball HR A naturally acquired quotidian-type malaria in man transferable to monkeys.Science. 1965; 149: 865-965Crossref PubMed Scopus (209) Google Scholar Previous experimental P knowlesi infections in humans had revealed the daily fever pattern of this parasite and tests had also shown that rhesus macaques (Macaca mulatta) infected with P knowlesi developed severe disease and often died. This first known zoonotic infection was confirmed to be P knowlesi by experimental inoculation—by use of blood from the infected person—of seven other individuals (who subsequently developed daily fevers) and three rhesus macaques, all of which subsequently died. The possibility of zoonotic malaria had major implications for ongoing malaria elimination and eradication efforts and sparked a massive research project in the jungles where the zoonosis had likely occurred (central Pahang).3Warren M Cheong WH Fredericks HK Coatney GR Cycles of jungle malaria in west Malaysia.Am J Trop Med Hyg. 1970; 19: 383-393Crossref PubMed Scopus (33) Google Scholar Blood was collected from 1117 participants living in the area and M mulatta monkeys were subsequently inoculated. None showed signs of illness. Although it was apparent that P knowlesi could infect humans, the findings from this investigation led many to believe that this only occurred in rare circumstances.3Warren M Cheong WH Fredericks HK Coatney GR Cycles of jungle malaria in west Malaysia.Am J Trop Med Hyg. 1970; 19: 383-393Crossref PubMed Scopus (33) Google Scholar More than 30 years later, investigations into an abnormally high burden of Plasmodium malariae uncovered a large focus of misdiagnosed P knowlesi infections in Malaysian Borneo.4Singh B Sung LK 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 (769) Google Scholar Since then, human P knowlesi infections have been identified in most other nations in southeast Asia, although the heaviest apparent burden continues to exist in northern Borneo.5Singh B Daneshvar C Human infections and detection of Plasmodium knowlesi.Clin Microbiol Rev. 2013; 26: 165-184Crossref PubMed Scopus (310) Google Scholar Most cases have been detected through passive case detection, leaving questions about the true burden of the disease in endemic areas. An impressive cross-sectional study by Kimberley Fornace and colleagues,6Fornace KM Brock PM Abidin TR et al.Environmental risk factors and exposure to the zoonotic malaria parasite Plasmodium knowlesi across northern Sabah, Malaysia: a population-based cross-sectional survey.Lancet Planet Health. 2019; 3: e157-e158Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar in The Lancet Planetary Health, provides the first detailed description of the overall burden of P knowlesi across a wide geographical region that is endemic for the disease (four districts in northern Sabah of Malaysian Borneo). Approximately 5% of the total surveyed population was seropositive for P knowlesi. Predictors of exposure included male sex, older age groups, reported contact with macaques, and reported activities in forested areas. Environmental attributes that were positively associated with P knowlesi exposure included living near irrigated rice paddy fields and pulpwood plantations, and near fragmented oil palm plantations. Participants living near fragmented forests and at higher geographical elevations were less likely to be seropositive for P knowlesi. Contact patterns between humans, mosquito vectors, and macaques are influenced by movement and land use patterns across heterogeneous environments. The movement ranges of human, macaque, and mosquito populations are likely to span different spatial scales. The most appropriate spatial scale for predicting risk of exposure to P knowlesi is therefore unclear. Rather than choosing arbitrary spatial units for use in their model, Fornace and colleagues measured environmental variables at radii ranging from 100 m to 5000 m around participant households and used a data mining approach to choose a best fitting model. This approach could usefully be implemented with many other datasets and with different disease systems. Some key questions remain unanswered. Although it is clear that humans can acquire this infection from macaques, human-to-human transfer in nature has not been established. Further basic science and ecological research into this disease system is warranted. P knowlesi infections appear to be relatively rare and heterogeneously distributed, but it is possible that low-density infections are missed. Methods that are designed to detect low-density infections7Imwong M Hanchana S Malleret B et al.High-throughput ultrasensitive molecular techniques for quantifying low-density malaria parasitemias.J Clin Microbiol. 2014; 52: 3303-3309Crossref PubMed Scopus (151) Google Scholar might be informative for understanding the epidemiology of P knowlesi. Serological markers can be useful for measuring historical disease burdens, and are perhaps especially useful in situations where infections are rare. Serological work on P knowlesi is promising, but continued work on the longevity and seroreactivity of antigenic responses to the parasite are needed. In this study, the authors attempted to measure only recent exposure. However, it is not immediately clear why exposure would increase (almost linearly) with age. This might be the result of behavioural differences across age groups, repeated exposure across the lifespan, or a combination of both factors. Although globally rare, P knowlesi malaria will probably continue to have public health significance at least for northern Borneo, where it is the largest overall contributor to malaria8WHO Regional Office for Western PacificExpert consultation on Plasmodium knowlesi malaria to guide malaria elimination strategies, Kota Kinabalu, Malaysia, 1–2 March 2017: meeting report. WHO Regional Office for the Western Pacific, Manila2017Google Scholar and where the landscape is quickly changing. Malaria elimination is being considered by most nations in this region9WHOEliminating malaria in the greater Mekong subregion: united to end a deadly disease.http://www.who.int/malaria/publications/atoz/eliminating-malaria-greater-mekong/en/Date: November, 2016Date accessed: March 19, 2019Google Scholar but the primary focus has been on P falciparum, with a growing interest in Plasmodium vivax. This zoonotic malaria, which exists at extremely high prevalence in some macaque populations,10Lee K-S Divis PCS Zakaria SK et al.Plasmodium knowlesi: reservoir hosts and tracking the emergence in humans and macaques.PLoS Pathogens. 2011; 7: e1002015Crossref PubMed Scopus (221) Google Scholar poses unique challenges that will need to be addressed if all forms of malaria are to be eliminated. I declare no competing interests. Environmental risk factors and exposure to the zoonotic malaria parasite Plasmodium knowlesi across northern Sabah, Malaysia: a population-based cross-sectional surveyAlthough few infections were detected, P knowlesi exposure was observed in all demographic groups and was associated with occupational factors. Results suggest that agricultural expansion and forest fragmentation affect P knowlesi exposure, supporting linkages between land use change and P knowlesi transmission. Full-Text PDF Open Access