Plasmodium knowlesi

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A Microbial Biorealm page on the genus Plasmodium knowlesi

Classification

Eukaryota, Alveolata, Apicomplexa, Aconoidasida, Haemosporida, Plasmodium, knowlesi

Description and significance

Plasmodium knowlesi is one of 5 known strains of malaria and is the most recently discovered strain of the group. Initially discovered in 1927 by Giuseppe, the parasite originally caused malaria in long-tailed and pig-tailed macaques. However, more recently P. knowlesi has been a popular source of malaria in humans due to urban development and increased interactions with forest fringes. In certain areas of South East Asia it accounts for up to 70% of all malaria cases. Plasmodium knowlesi can be transmitted to humans both directly, by the bite of an infected macaques, or indirectly through the bite of an infected mosquito. Plasmodium knowlesi has health, social and economic consequences for the regions affected by it. Although treatable, malaria continues to be the most important cause of fever and morbidity in tropical regions of the world. Plasmodium knowlesi undergoes asexual erythrocytic cycle replication in a 24 hour time period and therefore is known to cause sever and rapid cases of malaria in humans upon infection.

Genome structure

There are currently 5 strains of Plasmodium knowlesi that have been archived. P. knowlesi has 14 chromosomes on which a total of 5,102 protein-encoding genes have been identified. Unlike other Plosmodium species, (G+C) - rich repeat regions containing intrachromosomal telomeric sequences (ITSs, containing the sequence GGGTT[T/C]A) are found at multiple sites in P. knowlesi chromosomes. These sequences may be templates for the recombinations that result in gene conversion among variant antigen genes. ITSs are also thought to play a role in transcriptional control. Another unique feature of P. knowlesi is that it contains five distinct gene families with 4–15 paralogous members of unknown function. P. knowlesi does not have any plasmids.
Acquisition of host proteins, and thus the ability to mimic their function, has been observed in many bacterial and viral pathogens. Malaria parasites, such as P. knowlesi, are known to have a potential immunomodulatory role either by secreting functional homologues of host molecules or by binding to host antigen-presenting cells. P. knowlesi is the first strain observed in which a malaria protein has acquired host peptide sequences that are likely to be on the infected cell surface and thus may interact with the host. The mechanism by which Plasmodium knowlesi acquires these host sequences has yet to be discovered.

Cell structure, metabolism & life cycle

The Plasmodium knowlesi parasite replicates and completes a blood stage life cycle in 24-hour cycles. This results in fairly high loads of parasite densities in a very short period of time. Rapid replication makes P. knowlesi a potentially extremely severe disease if it remains untreated in the body. Infection begins when sporozoites, the infective stages, are injected in to the body by a mosquito and are circulated throughout body until they invade liver hepatocytes. It is in the liver that sporozoites undergo exoerythrocytic schizogony - a phase of asexual multiplication –, which results in the production of many uninucleate merozoites. These merozoites exit the liver, enter the bloodstream, and then proceed to invade red blood cells. Once in the cells, P. knowlesi initiates a second phase of asexual multiplication called erythrocytic schizogony, which results in the production of about 8-16 merozoites that then invade new red blood cells. This phase is responsible for the disease malaria. Erythrocytic schizogony is cyclical and is repeated almost indefinitely. As the infection progresses, some young merozoites develop into male and female gametocytes that circulate in the peripheral blood until female mosquitoes take them up during feeding. Within the mosquito the gametocytes mature into male and female gametes, fertilization occurs and a motile zygote is formed within the mosquito gut, beginning a process known as sporogony. The motile zygote penetrates the gut wall and becomes a oocyst within which another phase of multiplication occurs resulting in the formation of sporozoites that migrate to the salivary glands of a mosquito and are injected when the mosquito feeds on a new host. These stages of Plasmodium knowlesi are microscopically indistinguishable from Plasmodium malariae and the early trophozoites are identical to those of Plasmodium falciparum.

Ecology (including pathogenesis)

In 1957, it was suggested by Garnham et al. that P. knowelsi could be the fifth species capable of causing endemic malaria in humans. Since 2004, there have 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. Although it is primarily characterized as a primate parasite, increased macaques-human interaction due to the spread of urban development and deforestation of jungles has caused P. knowlesi to become a more poplar strain of malaria.
Two possible modes of transmission exist, monkey-human and mosquito-human. In both cases parasites can be seen in blood samples between 10 – 12 days after infection. The pathogenesis of the disease is identical to the Plasmodium knowlesi's lifecycle. In a mosquito, the infection begins when the mosquito ingests parasitic gametocytes (either microgametocytes of macrogametocytes), which have been formed in the mammalian host. Gametocytes then mature in to either microgametes or microgametes which then fertilize forming zygotes within the midgut of the misquito. Zygotes then mature into ookinetes, motile zygotes, and later oocysts. Finally the oocysts develop and release sporozoites- motile infective forms of sporozoans, which move to the salivary gland of the mosquito to initiate an asexual cycle in the new host.
In humans, P. knowlesi developes in two stages; in the liver and in the blood. Upon injection, sporozoites invade the bloodstream. Sporozoites that travel to the liver undergo asexual reproduction to become schizonts--multinucleate sporozoan--and then later merozoites, which are small ameboid sporozoan trophozoites capable of initiating a new sexual or asexual cycle of development in liver cells. Immature trophozoites then take one of two paths. In the first path cells can enter the erythrocytic cycle and become mature trophozoites, which become schizonts and then rupture releasing merozoites. In the second path, mature trophozoites differentiate into sexual erythrocytic stages (gametocytes), which can be ingested by mosquitos. Blood stage parasites are responsible for the clinical manifestations of the disease. P. knowlesi infection does not relapse because the parasite has no liver hypnozoite stage.
Symptoms of malaria usually appear within 10-15 days after a person is infected and develop in 3 stages. During stage 1 patents exhibit chills (caused by ruptured blood cells), nausea, headache, and possibly vomiting. In stage 2 fever is induced. In stage 3, patents start sweating as Plasmodium knowlesi starts to multiply more rapidly inside its host. If not treated promptly malaria can cause sever illness and is often fatal. 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%.
Infection of P. knowlesi strain malaria is diagnosed by examining thick and thin blood films in the same way as other malarias are diagnosed. Because the morphology of Plasmodium knowlesi is so similar to that of Plasmodium malariae, PCR assay and molecular characterization are the only sure way to detect and diagnose P. knowlesi malaria. Unfortunately, PCR methodology is slow, expensive, and requires very specialized equipment. Rapid treatment of a P. knowlesi infection is imperative because of the parasite's 24 hour erythrocytic cycle which can result in very high parasite density. Chloroquine and primaquine are two drugs that have been able to treat P. knowlesi infections successfully. Other modes of prevention include mosquito nets and insecticide spray.

Interesting feature

Malaria is considered to be one of - if not the - world’s most devastating human parasitic infection. Malaria affects over 40% of the world’s population. It has been estimated that there are 350-500 million cases of malaria worldwide. Although it is not as popular as other diseases- especially in the western hemisphere- such as cancer and AIDS, malaria is a bigger killer than either of these competitors. Malaria kills in one year what AIDS kills in 15 years. For every death caused by HIV/AIDS there are about 50 deaths caused by malaria. Increasing drug resistance has exacerbated the problem. Finding new drugs that are able to effectively treat malaria has been a popular genre of study in the biomedical and pharmaceutical fields.

References

Cox, Francis E.G. "History of the Discovery of the Malaria Parasites and Their Vectors." Annals of Microbiology and Antimicrobials. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine,, 1 Feb. 2010. Web. 31 Oct. 2011. <http://www.parasitesandvectors.com/content/3/1/5>.

"DPDx - Malaria." Microsoft Internet Information Server. Web. 31 Oct. 2011. <http://dpd.cdc.gov/dpdx/html/Malaria.htm>.

"KEGG GENOME: Plasmodium Knowlesi." KEGG Genome: Plasmodium Knowlesi. KEGG. Web. 31 Oct. 2011. <http://www.genome.jp/kegg-bin/show_organism?org=pkn>.

Lau Y-L, Tan L-H, Chin L-C, Fong M-Y, Noraishah Abdul-Aziz M, Rohela M. Plasmodium knowlesi reinfection in human [letter]. Emerg Infect Dis [serial on the Internet]. 2011 Jul [date cited]. http://dx.doi.org/10.3201/eid1707.101295

Pain, A. "The Genome of the Simian and Human Malaria Parasite Plasmodium Knowlesi : Article : Nature." Nature Publishing Group : Science Journals, Jobs, and Information. 30 July 2008. Web. 31 Oct. 2011. <http://www.nature.com/nature/journal/v455/n7214/full/nature07306.html>.

"Plasmodium Knowlesi." NCBI. Web. 30 Oct. 2011. <http://http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=5850&lvl=3&p=mapview&p=has_linkout&p=blast_url&p=genome_blast&lin=f&keep=1&srchmode=1&unlock>.

Rao, T. V. "Malaria." Upload & Share PowerPoint Presentations and Documents. Web. 31 Oct. 2011. <http://www.slideshare.net/doctorrao/malaria-1478424>.

Wolcott, Gordon B. "Chromosome Studies in the Genus Plasmodium - Wolcott - 2007 - Journal of Eukaryotic Microbiology." Wiley Online Library. The Journal of Eukaryotic Microbiology, 29 Apr. 2007. Web. 31 Oct. 2011. <http://onlinelibrary.wiley.com/doi/10.1111/j.1550-7408.1957.tb02483.x/abstract>.