Plasmodium knowlesi is a primate malaria parasite commonly found in Southeast Asia. It causes malaria in long-tailed macaques (Macaca fascicularis), but it may also infect humans, either naturally or artificially.
Sinton and Mulligan 1933
Plasmodium knowlesi is the sixth major human malaria parasite (following the division of Plasmodium ovale into 2 subspecies). It may cause severe malaria as indicated by its asexual erythrocytic cycle of about 24 hours, with an associated fever that typically occurs at the same frequency (i.e. the fever is quotidian). This is an emerging infection that was reported for the first time in humans in 1965. It accounts for up to 70% of malaria cases in certain areas in South East Asia where it is mostly found. This parasite is transmitted by the bite of an Anopheles mosquito. Plasmodium knowlesi has health, social and economic consequences for the regions affected by it.
Like other Plasmodium parasites, P. knowlesi has a life cycle that requires it be passed back and forth between mammalian hosts and insect hosts. Primates are infected through the bite of an infected Anopheles mosquito which carries a parasite stage called the sporozoite in its salivary glands. Sporozoites follow the blood stream to the primate liver where they develop and replicate over 5 to 6 days before bursting, releasing their daughter cells called merozoites into the blood (unlike the related P. vivax, P. knowlesi does not make latent hypnozoites in the liver). The merozoites in the blood attach to and invade the primate's red blood cells. Inside the red blood cell, the parasite progresses through several morphologically distinguishable stages, called the ring stage, the trophozoite, and then the schizont. The schizont-infected red blood cells eventually burst, releasing new merozoites into the blood stream which infect new red blood cells and continue the cycle. P. knowlesi completes this red blood cell cycle every 24 hours, making it uniquely rapid among primate-infecting Plasmodium species (which generally take 48 or 72 hours). Some parasites that invade red blood cells instead enter a sexual cycle, developing into microgametocytes or macrogametocytes. These gametocytes remain in the blood to be ingested by mosquitoes.
A mosquito ingests gametocytes when it takes a blood meal from an infected primate host. These are either microgametocytes (which are male gametocytes) or macrogametocytes (which are female gametetocytes). These gametocytes mature into microgametes and macrogametes respectively, and then fertilize to form zygotes within the midgut of the mosquito. The zygotes mature into ookinetes, then into oocysts. Finally, the oocysts mature to release sporozoites which move to salivary gland of the mosquito. This process in the mosquito takes 12 to 15 days.
The genome of P. knowlesi consists of 23.5 megabases of DNA separated into 14 chromosomes. This contains approximately 5200 protein-coding genes, 80% of which have orthologs present in P. falciparum and P. vivax. The genome contains two large gene families that are unique to P. knowlesi: SICAvar (schizont-infected cell agglutination variant) and Kir (knowlesi interspersed repeat).
Evolution and taxonomyEdit
Despite its morphological similarity to P. malariae, P. knowlesi is most closely related to the human parasite P. vivax. Based on a Bayesian coalescent approach the most probable time of evolution of P. knowlesi is 257,000 years ago (95% range 98,000–478,000). A phylogenetic tree comparing the Plasmodium species that infect humans is shown below:
The population of P. knowlesi parasites is more genetically diverse than that of P. falciparum or P. vivax. Within P. knowlesi there are three genetically distinct subpopulations. Two are present in the same areas of Malaysian Borneo; one infects long-tailed macaques while the other infects pig-tailed macaques. The third is geographically separated and comes from the Malaysian Peninsula.
Three subspecies of P. knowlesi have been described based on differences in their appearance in stained blood films: P. knowlesi edesoni, P. knowlesi sintoni, and P. knowlesi arimai, which were isolated from Malaysia, Java, and Taiwan respectively. The relationship between these described subspecies and the populations described in the modern literature is not clear.
Plasmodium knowlesi is found throughout Southeast Asia, where it primarily infects the primates long-tailed macaques, pig-tailed macaques, and banded-leaf monkeys, as well as the mosquito vectors Anopheles hackeri, Anopheles latens, Anopheles cracens, Anopheles balabacensis, Anopheles dirus, and Anopheles introlatus. P. knowlesi is rarely found outside of Southeast Asia, likely because the species it infects are restricted to that region.
This parasite is mostly found in South East Asian countries particularly in Borneo, Cambodia, Malaysia, Myanmar, Philippines, Singapore, Thailand and neighboring countries and it appears to occur in regions that are reportedly free of the other four types of human malaria. Infective mosquitoes are restricted to the forest areas. Non-infective mosquitoes are typically found in the urban areas but transmission may occur due to the abundance of mosquitoes in this region. particularly Malaysia, but there are also reports on the Thai-Burmese border. One fifth of the cases of malaria diagnosed in Sarawak, Malaysian Borneo are due to P. knowlesi.
Theoretically there are four modes of transmission: from an infected mosquito to another monkey, from an infected monkey to a human, from an infected human to another human and from an infected human back to a monkey. In practice human malaria appears to be almost entirely due to monkey to human transmission.
The known vectors belong to the genus Anopheles, subgenus Cellia, series Neomyzomyia and group Leucosphyrus. Mosquitoes of this group are typically found in forest areas in South East Asia but with a greater clearing of forest areas for farmland, humans are increasingly becoming exposed to these vectors.
Within the monkey population in Peninsular Malaysia, Anopheles hackeri is believed to be the main vector of P. knowlesi: although A. hackeri is capable of transmitting malaria to humans, it is not normally attracted to humans and seems unlikely to be an important vector for transmission to humans.
Anopheles latens is attracted to both macaques and humans and has been shown to be the main vector transmitting P. knowlesi to humans in the Kapit Division of Sarawak, Malaysian Borneo. Anopheles cracens has also been reported as a vector of P. knowlesi. Both species of mosquitoes have been shown to contain as many as 1,000 sporozoites suggesting that they may be efficient vectors. A study of potential vectors in Malayasia suggests that Anopheles cracens may be an important vector of P. knowlesi.
Role in human diseaseEdit
P. knowlesi can cause both uncomplicated and severe malaria in humans. Symptoms typically begin approximately 11 days after an infected mosquito has bitten a person and the parasites can be seen in the blood between 10 – 12 days after infection. Symptoms of P. knowlesi in humans include headache, fever, chills and cold sweats. Singh et al. (2004) showed clinical symptoms in 94 patients with single species P. knowlesi infection at Kapit Hospital, Sarawak, Malaysian Borneo. Symptoms included fever, chills, and rigor in 100% of patients, headache in 32%, cough in 18%, vomiting in 16%, nausea in 6%, and diarrhea in 4%.
Severe P. knowlesi malaria resembles severe malaria caused by P. falciparum. P. knowlesi parasites replicate particularly quickly; dangerously high parasitemias and severe disease can develop rapidly. People may experience acute kidney injury, hyperparasitemia, jaundice, shock, and respiratory distress. Metabolic acidosis is uncommon, but can occur is particularly severe cases. Unlike P. falciparum malaria, severe P. knowlesi malaria rarely affects children, and rarely causes coma.
Asexual cycle of the parasite in humans and its natural host macaque is about 24 hours. Hence the disease may be called quotidian malaria, in concert with designation of tertian malaria and quartan malaria. In addition to a lab diagnosis using PCR assay, knowlesi malaria may also present itself with elevated levels of C-reactive protein and thrombocytopenia.
As with other causes of malaria, P. knowlesi infection is traditionally diagnosed by examining stained blood films under a microscope. Complicating proper diagnosis, several P. knowlesi life stages are indistinguishable by microscopy from the more benign P. malariae. Other stages resemble P. falciparum and P. vivax, and misdiagnosis as either is common. While some rapid diagnostic tests can detect P. knowlesi, they tend to have poor sensitivity and specificity and are therefore not always reliable. Detection of nucleic acid by PCR or real-time PCR is the most reliable method for detecting P. knowlesi, and differentiating it from other Plasmodium species infection; however due to the relatively slow and expensive nature of PCR, this is not available in many endemic areas. Loop-mediated isothermal amplification methods of P. knowlesi detection have also been developed, but are not yet widely used.
Because P. knowlesi takes only 24 hours to complete its erythrocytic cycle, it can rapidly result in very high levels of parasitemia with fatal consequences. For those with uncomplicated malaria, the World Health Organization recommends treatment with artemisinin-based combination therapy (ACT) or chloroquine. For those with severe malaria, the World Health Organization recommends administration of intravenous artesunate for at least 24 hours, followed by ACT treatment. Since P. knowlesi infection of humans has been recognized for a short time, relatively few studies have been done on P. knowlesi sensitivity to various antimalarial drugs. However in studies that have been done, combinations of chloroquine and primaquine, artesunate and mefloquine, artemether and lumefantrine, and chloroquine alone have all been found to be effective treatments for uncomplicated P. knowlesi malaria. There is no evidence of P. knowlesi developing resistance to current antimalarials.
Risk of P. knowlesi infection is reduced in households that practice indoor residual spraying of insecticide. As with other mosquito-borne infections, sleeping under bed nets may provide some protection against infection; however, in one study in Sabah, Malaysia, use of bed nets had little effect on infection risk.
A single post mortem case has been described to date The patient was a male who became unwell 10 days after exposure. After four days he presented acutely unwell to a hospital. He was found to have a raised eosinophil count, to be thrombocytopaenic, hyponatraemic with an elevated blood urea, potassium, lactate dehydrogenase and amino transferase values. Dengue fever was suspected but ruled out on investigation. Malarial parasites were seen on the blood film and later identified as Plasmodium knowlesi by PCR. At post mortem the liver and spleen were enlarged. The brain and endocardium showed multiple petechial haemorrhages. The lungs had features consistent with acute respiratory distress syndrome. Histological examination showed sequestration of pigmented parasitized red blood cells in the vessels of the cerebrum, cerebellum, heart and kidney without evidence of chronic inflammatory reaction in the brain or any other organ examined. The spleen and liver had abundant pigment containing macrophages and parasitized red blood cells. The kidney had evidence of acute tubular necrosis. Endothelial cells in heart sections were prominent. Brain sections were negative for intracellular adhesion molecule-1.
The overall post mortem picture was very similar to that found in cases of Plasmodium falciparum. There were important differences including the absence of coma despite petechial haemorrhages and parasite sequestration in the brain.
P. knowlesi is the most common cause of malaria in Malaysia. However, cases of P. knowlesi malaria have been reported in most countries of Southeast Asia as well as travelers from the region. Reports of P. knowlesi malaria have increased substantially in the 21st century; this is likely due to increases in capacity to accurately diagnose malaria cases, awareness of P. knowlesi as a cause of human disease, and proximity of humans to the primate and mosquito hosts.
Infection with P. knowlesi is associated with several socioeconomic and lifestyle factors that bring people into close contact with primate and mosquito hosts. Those who live near dense forest cover and low elevation are more likely to be infected by P. knowlesi. Infections are also more common in people over the age of 15, and those who work on a farm or palm oil plantation. As with P. vivax infection, people with Glucose-6-phosphate dehydrogenase deficiency are less likely to be infected by P. knowlesi than those without the condition.
Humans who work at the forest fringe or enter the rainforest to work are at risk of infection. With the increasing popularity of deforestation and development efforts in South East Asia, many macaques are now coming in close and direct contact with humans. Hence more and more people who live in the semi-urban areas are being found to be infected with knowlesi malaria. 2,584 cases of this type of malaria were reported in Malaysia in 2014.
History of discoveryEdit
The first person to see P. knowlesi was probably the Italian Giuseppe Franchini in 1927 when he was examining the blood of Macaca fascicularis and he noted that it differed from Plasmodium cynomolgi and Plasmodium inui. It was later seen by Campbell[ambiguous] in 1931 in a long-tailed macaque imported from Singapore to the Calcutta School of Tropical Medicine and Hygiene in India. Campbell was interested in another disease, kala azar, and was working under Napier.[ambiguous] Napier inoculated the strain into three monkeys, one of which was a rhesus macaque (Macaca mulatta), which developed a fulminating infection. Knowing that the Protozoological Department were looking for a monkey malaria strain, they handed the original infected monkey to Biraj Mohan Das Gupta, who was the assistant of Robert Knowles. Dr Das Gupta maintained the species by serial passage in monkeys until Dr Knowles returned from leave. In 1932, Knowles and Das Gupta described the species in detail for the first time and showed that it could be transmitted to man by blood passage, but failed to name it. It was named by Sinton and Mulligan in 1932 after Dr Knowles. From early in the 1930s to 1955, P. knowlesi was used as a pyretic agent for the treatment of patients with neurosyphillis.
In 1957, it was suggested by Garnham et al. that P. knowlesi could be the fifth species capable of causing endemic malaria in humans.
In 1960, American parasitologist Don E. Eyles and his supervisor, G. Robert Coatney (1902–1990) worked under the National Institutes of Health to carry out experiments on rhesus macaques in a Memphis laboratory with the assumption that humans were not susceptible to “monkey malaria.” Early research had concluded that macaques could not host Plasmodium vivax, the human malaria parasite. This led Eyles and Coatney to begin working with Plasmodium cynomolgi, a parasite similar enough to P. vivax to model the human malaria infection. The two exposed themselves to the infection, noting the causal itchy bite as a mere annoyance; however, Eyles fell ill with fever soon after the experiment. It was not until several days later that the two accepted the possibility that Eyles may have contracted malaria. Examination of blood films would confirm that it was in fact possible to contract “monkey malaria.”
In 1965, the first case of a naturally occurring infection of knowlesi malaria in humans was reported in a 37-year-old male who worked as a surveyor for the U.S. Army Map Service. After carrying out a short trip to peninsular Malaysia, he traveled to Thailand, where he began to feel ill. Although the infecting parasite was initially identified as P. falciparum, one day later it was then identified as P. malariae and it was only confirmed to be P. knowlesi after infected blood was used to inoculate rhesus monkeys. In observing the local population where the infection took place, Dr. G. Robert Coatney and other researchers found that they were regularly exposed to the parasite, and, further, were joint hosts of the parasite along with the local monkey populations. This observation led Coatney to declare that monkey malaria is a “true zoonosis.” Prior to arranging the surveyor’s treatment, Coatney had samples of his blood sent back to his lab in Atlanta, where they would be used to infect human prison volunteer inmates and monkeys. A second report emerged in 1971 about the natural infection of a man in Malaysia with Plasmodium knowlesi followed by the description of a large focus of human infections in the Kapit Division of Sarawak, Malaysian Borneo. This was made possible due to the development of molecular detection assays which could differentiate between Plasmodium knowlesi and the morphologically similar Plasmodium malariae. Since 2004, there has been an increasing number of reports of the incidence of P. knowlesi among humans in various countries in South East Asia, including Malaysia, Thailand, Singapore, the Philippines, Vietnam, Myanmar and Indonesia.
Work with archival samples has shown that infection with this parasite has occurred in Malaysia at least since the 1990s and it is now known to cause 70% of the malaria cases in certain areas of Sarawak.
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