Plasmodium knowlesi

Plasmodium knowlesi
Scientific classification
Kingdom:	Protista
Phylum:	Apicomplexa
Class:	Aconoidasida
Order:	Haemosporida
Family:	Plasmodiidae
Genus:	Plasmodium
Species:	knowlesi
Binomial name
Plasmodium knowlesi

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.

Plasmodium knowlesi is the fifth major human malaria parasite. It may cause severe malaria as indicated by its asexual erythrocytic cycle of about 24 hours.^[1][2][3] The typical fever becomes quotidian.^[1] This is an emerging infection that was reported for the first time in humans in 1965.^[1] It accounts for up to 70%^[4] of malaria cases in South East Asia where it is mostly found. This parasite is transmitted by the bite of an Anopheles leucosphyrus mosquito.^[4] Plasmodium knowlesi has health, social and economic consequences for the regions affected by it.

Contents 1 History of Discovery 2 Life cycle 3 Epidemiology 4 Vectors 5 Clinical 6 Diagnosis 7 Treatment 8 Public health, Prevention strategies and Vaccines 9 Useful Web Links 10 Plasmodium knowlesi genome data 11 References

History of Discovery

In 1931, Plasmodium knowlesi was first recognized as a lethal infection of long tailed macaques.^[5] From early in the 1930’s, P. knowlesi was used as a pyretic treatment for patients with neurosyphillis.^[5] In 1932 – an inoculation experiment using human blood revealed that these parasites could also infect humans.^[5]

In 1965, the first case of a naturally occurring infection of knowlesi malaria in humans was reported in an American man who had returned from visiting peninsular Malaysia.^[6] 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 the infected blood was used to inoculate Rhesus monkeys.^[5] A second report emerged in 1971 about the natural infection of a man in Malaysia with Plasmodium knowlesi^[5] However, since 2004, there have been an increased number of reports in the incidence of P. knowlesi among humans in South East Asia.^[7]

Work with archival samples have shown that infection with this parasite has occurred in Malaysia at least since the 1950s'^[8] and it is now known to cause 70% of the malaria cases in Sarawak.^[9]

Life cycle

Plasmodium knowlesi parasite replicates and completes its blood stage cycle in 24 hour cycles^[3] resulting in fairly high loads of parasite densities in a very short period of time. This makes it a potentially very severe disease if it remains untreated. Life cycle: merozoite → schizont → trophozoites. These stages are microscopically indistinguishable from Plasmodium malariae.

Mosquito stages:^[10] A mosquito ingests gametocytes, which have been formed in the mammalian host. These are either microgametocytes (which give rise to male gametocytes) or macrogametocytes (which give rise to female gametocytes). These gametocytes mature into microgametes and macrogametes respectively, and then form zygotes within the midgut of the mosquito by fertilization. The zygotes mature into ookinetes, then into oocysts. Finally, the oocysts mature into sporozoites which move to salivary gland of the mosquito.

Summary: gametocyte → (microgamete or macrogamete) → zygote → ookinete → oocyst → sporozoites.

In man: exoerythrocytic stage (in the liver):^[10] The sporozoites are injected into humans when the mosquito bites and they travel to the liver through blood stream and undergo asexual reproduction to become merozoites through schizonts in the liver cell. Hypnozoites in the liver has not yet been found.

Summary: sporozoites → schizonts → merozoites.

In man: erythrocytic stage (in the blood):^[10] Merozoites are unleashed into the blood stream to infect into the erythrocytes constituting one asexual cycle of infection of the erythrocytes. Some merozoites become microgametocytes or macrogametocytes after infection of the erythrocytes. These remain in the blood to be ingested by mosquitoes.

Summary: Merozoite → trophozoite → schizont → merozoites.

Epidemiology

P. knowlesi infection is normally considered a parasite of long-tailed (Macaca fascicularis) and pig-tailed (Macaca nemestrina) macaques ^[7][11] but 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.^[7] Hence more and more people who live in the semi-urban areas are being found to be infected with knowlesi malaria.

This parasite is mostly found in South East Asian countries particularly in Borneo, 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.^[1][12] particularly Malaysia,^[5] but there are also reports on the Thai-Burmese border.^[2] One fifth of the cases of malaria diagnosed in Sarawak, Malaysian Borneo are due to P. knowlesi.^[5]

Plasmodium knowlesi is less prevalent in Africa. This may be because many West African blacks lack the Duffy antigen - a protein on the surface of the red blood cell that the parasite to uses to invade.^[6]

Vectors

Theoretically there are four modes of transmission: from an infected monkey 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.^[7] In practice human malaria appears to be almost entirely due to monkey to human transmission.

Anopheles crucens 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.^[7]

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,^[13] it is not normally attracted to humans and seems unlikely to be an important vector for transmission to humans.^[14]

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.^[15]

Anopheles leucosphyrus is known to transmit P. knowlesi from monkeys to humans.^[3] An. leucosphyrus is 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 this vector.

Clinical

Two possible modes of transmission to humans have been proposed: either from an infected monkey to a human or from an infected human to another human.

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.^[16] The parasite may multiply rapidly resulting in very high parasite densities that may be fatal.^[16]

Although the current infection rate with Plasmodium knowlesi is relatively low, one risk it presents is misdiagnosis with other forms of malarial parasites such as P. malariae especially when microscopy is used. P. knowlesi is more accurately distinguished from P. malariae using PCR assay and molecular characterization.

Symptoms of P. knowlesi in humans include headache, fever, chills and cold sweats.^[17] Singh et al. (2004)^[5] showed clinical symptoms in 94 patients with single species P. knowlesi infection at Kapit Hospital, 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%. Asexual cycle of the parasite in humans and its natural host macaque is about 24 hours.^[1][2][3] Hence the disease may be called quotidian malaria,^[1] in concert with designation of tertian malaria and quartan malaria.^[10] In addition to a lab diagnosis using PCR assay, knowlesi malaria may also present itself with elevated levels of C-reactive protein and thrombocytopenia.

This parasite causes non-relapsing malaria^[18] due to lack of hypnozoites in its exoerythrocytic stage.^[19]

While infection with this organism is normally not serious, life threatening complications or even death may occur in a minority of cases. The most common complications are respiratory distress, abnormal liver function including jaundice and renal failure. Mortality in one series of cases was about 2%.^[20]

Diagnosis

P. knowlesi infection is diagnosed by examining thick and thin blood films in the same way as other malarias. The appearance of P. knowlesi is similar to that of P. malariae and is unlikely to be correctly diagnosed except by using molecular detection assays^[5] in a malaria reference laboratory.

The morphology of Plasmodium knowlesi is similar to that of Plasmodium malariae. P. malariae is characterized by a compact parasite (all stages) and does not alter the host erythrocyte's shape or size or cause enlargement. Elongated trophozoites stretching across the erythrocyte, called band forms, are sometimes observed. Schizonts will typically have 8-10 merozoites that are often arranged in a rosette pattern with a clump of pigment in the center.^[21]

Rapid diagnostic tests kits may or may not recognize P. knowlesi because of their specificity.

Currently PCR assay and molecular characterization are the most reliable methods for detecting and diagnosing P. knowlesi infection. PCR identifies the parasite protein but this technique is not rapid and cannot be used for routine identification. PCR is also expensive and requires very specialized equipment.^[5]

Treatment

Because P. knowlesi takes only 24 hours to complete its life cycle, it can result in very high parasite density quickly and may be fatal in humans. For this reason early treatment is advised. It responds well to treatment with chloroquine and primaquine.^[5] It has been advised that those who reside in or have traveled to the South East Asia should be treated as intensively when found to be suffering from malaria.^[3]

Public health, Prevention strategies and Vaccines

1. Mosquito bed nets; 2. Medication – Mefloquine, Chlorquine: 3. Vector control; 4. Residual spraying using insecticides.

Useful Web Links

• 1. CDC: cdc.gov/malaria, http://www.cdc.gov/EID/content/14/11/1750.htm
• 2. WHO: http://www.who.int/topics/malaria/en/
• 3. Short film on the discovery of the role of P. knowlesi in human malaria: http://www.abc.net.au/catalyst/stories/2533454.htm

Plasmodium knowlesi genome data

• GeneDB Plasmodium knowlesi

References