View source for Plasmodium knowlesi

{{Short description|Species of single-celled organism}}
{{Good article}}
{{Speciesbox
| image = Plasmodium knowlesi smears IDC.png
| image_caption = Giemsa-stained smears of ''Plasmodium knowlesi'' infecting human red blood cells
| genus = Plasmodium
| species = knowlesi
| authority = Sinton and Mulligan 1932
}}

'''''Plasmodium knowlesi''''' is a parasite that causes [[malaria]] in humans and other primates. It is found throughout [[Southeast Asia]], and is the most common cause of human malaria in [[Malaysia]]. Like other ''[[Plasmodium]]'' species, ''P. knowlesi'' has a life cycle that requires infection of both a mosquito and a warm-blooded host. While the natural warm-blooded hosts of ''P. knowlesi'' are likely various [[Old World monkey]]s, humans can be infected by ''P. knowlesi'' if they are fed upon by infected mosquitoes. ''P. knowlesi'' is a eukaryote in the phylum [[Apicomplexa]], genus ''Plasmodium'', and subgenus ''Plasmodium''. It is most closely related to the human parasite ''[[Plasmodium vivax]]'' as well as other ''Plasmodium'' species that infect non-human primates.

Humans infected with ''P. knowlesi'' can develop [[uncomplicated malaria|uncomplicated]] or [[severe malaria]] similar to that caused by ''[[Plasmodium falciparum]]''. Diagnosis of ''P. knowlesi'' infection is challenging as ''P. knowlesi'' very closely resembles other species that infect humans. Treatment is similar to other types of malaria, with [[chloroquine]] or [[artemisinin combination therapy]] typically recommended. ''P. knowlesi'' malaria is an emerging disease previously thought to be rare in humans, but increasingly recognized as a major health burden in Southeast Asia.

''P. knowlesi'' was first described as a distinct species and as a potential cause of human malaria in 1932. It was briefly used in the early 20th century to cause fever as a treatment for [[neurosyphilis]]. In the mid-20th century, ''P. knowlesi'' became popular as a tool for studying ''Plasmodium'' biology and was used for basic research, vaccine research, and drug development. ''P. knowlesi'' is still used as a laboratory model for malaria, as it readily infects the [[model organism|model]] primate the [[rhesus macaque]], and can be grown in [[cell culture]] in human or macaque blood.

==Life cycle==
[[File:Plasmodium life cycle CDC.tif|thumb|left|A diagram of the life cycle of ''Plasmodium'' species that infect humans]]
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 five to six days before bursting, releasing thousands of daughter cells called [[merozoite]]s into the blood (unlike the related ''P. vivax'', ''P. knowlesi'' does not make latent [[hypnozoite]]s in the liver).<ref name=Collins2012/><ref name=Butcher2016/> The merozoites in the blood attach to and invade the primate's [[red blood cell]]s. Inside the red blood cell, the parasite progresses through several morphologically distinguishable stages, called the ring stage, the [[trophozoite]], and the schizont. The schizont-infected red blood cells eventually burst, releasing up to 16 new merozoites into the blood stream that infect new red blood cells and continue the cycle.<ref name=Collins2012/><ref name=Coatney/> ''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).<ref name=Butcher2016/> Occasionally, parasites that invade red blood cells instead enter a sexual cycle, developing over approximately 48 hours into distinct sexual forms called microgametocytes or macrogametocytes.<ref name=Collins2012/><ref name=Coatney/> These gametocytes remain in the blood to be ingested by mosquitoes.<ref name=Collins2012/><ref name=Coatney/>

A mosquito ingests gametocytes when it takes a [[Hematophagy|blood meal]] from an infected primate host. Once inside the mosquito gut, the gametocytes develop into [[gamete]]s and then fuse to form a [[diploid]] zygote.<ref name=Collins2012>{{Cite journal |vauthors = Collins WE | title = ''Plasmodium knowlesi'': A Malaria Parasite of Monkeys and Humans | journal = Annual Review of Entomology | volume = 57 | pages = 107–121 | year = 2012 | pmid =  22149265| url = https://zenodo.org/record/1234957| doi = 10.1146/annurev-ento-121510-133540 }}</ref> The zygote matures into an [[ookinete]], which migrates through the wall of the mosquito gut and develops into an [[oocyst]].<ref name=Collins2012/><ref>{{cite journal|vauthors=Smith RC, Barillas-Mury C |title=''Plasmodium'' Oocysts: Overlooked Targets of Mosquito Immunity |date=December 2016 |volume=32 |issue=12 |pages=979–990 |doi=10.1016/j.pt.2016.08.012 |journal=Trends in Parasitology |publisher=Elsevier|pmid=27639778 |url=https://lib.dr.iastate.edu/ent_pubs/435 }}</ref> The oocyst then releases thousands of sporozoites, which migrate through the mosquito to the salivary glands.<ref name=Collins2012/> This entire process in the mosquito takes 12 to 15 days.<ref name=Butcher2016/>

==Cell biology==
{{Further|Plasmodium#Description}}
[[File:Plasmodium knowlesi merozoite.jpg|thumb|upright=0.75|A ''Plasmodium knowlesi'' merozoite attaching to a red blood cell]]
''P. knowlesi'' largely resembles other [[Plasmodium#Description|''Plasmodium'' species]] in its cell biology. Its genome consists of 23.5 [[megabase]]s of DNA separated into 14 [[chromosome]]s.<ref name=Garrido2018/> It contains approximately 5200 protein-coding genes, 80% of which have [[ortholog]]s present in ''P. falciparum'' and ''P. vivax''.<ref name=Garrido2018/> The genome contains two large gene families that are unique to ''P. knowlesi'': the SICAvar (schizont-infected cell agglutination variant) family, which is involved in displaying different [[antigen]]s on the parasite surface to evade the immune system, and the Kir (knowlesi interspersed repeat) family, involved in adhering parasitized red blood cells to blood vessel walls.<ref name=Garrido2018/>

As an [[apicomplexan]], ''P. knowlesi'' has several distinctive structures at its [[Anatomical terms of location#apical|apical end]] that are specialized for invading host cells. These include the large bulbous [[rhoptries]], smaller [[microneme]]s, and dispersed [[dense granule]]s, each of which secretes effectors to enter and modify the host cell.<ref>{{cite journal|doi=10.1016/j.pt.2013.03.003 |pmid=23570755 |title=Plasmodium rhoptry proteins: Why order is important|journal=Trends in Parasitology |volume=29 |issue=5|pages=228–36|year=2013|last1=Counihan|first1=Natalie A. |last2=Kalanon |first2=Ming |last3=Coppel |first3=Ross L.|last4=De Koning-Ward|first4=Tania F.}}</ref><ref name=Kemp2013>{{cite journal|doi=10.1111/1574-6976.12013|pmid=23186105|title=Subversion of host cellular functions by the apicomplexan parasites|journal=FEMS Microbiology Reviews|volume=37|issue=4|pages=607–31|year=2013|last1=Kemp|first1=Louise E.|last2=Yamamoto|first2=Masahiro|last3=Soldati-Favre|first3=Dominique|url=https://archive-ouverte.unige.ch/unige:28792/ATTACHMENT01|doi-access=free}}</ref> Like other apicomplexans, ''P. knowlesi'' also has two [[organelle]]s of [[Symbiogenesis|endosymbiotic origin]]: a single large [[mitochondrion]] and the [[apicoplast]], both of which are involved in the parasite's [[metabolism]].<ref name=Sheiner2013>{{cite journal |doi=10.1016/j.mib.2013.07.003|pmid=23927894|title=The metabolic roles of the endosymbiotic organelles of Toxoplasma and Plasmodium spp|journal=Current Opinion in Microbiology|volume=16|issue=4 |pages=452–8|year=2013|last1=Sheiner |first1=Lilach |last2=Vaidya |first2=Akhil B.|last3=McFadden|first3=Geoffrey I.|pmc=3767399}}</ref>

==Evolution and taxonomy==
Despite its morphological similarity to ''P. malariae'', ''P. knowlesi'' is most closely related to ''P. vivax'' as well as other ''Plasmodium'' species that infect non-human primates.<ref name=Lee2011/> The last common ancestor of all modern ''P. knowlesi'' strains lived an estimated 98,000 to 478,000 years ago.<ref name=Lee2011>{{cite journal | vauthors = Lee KS, Divis PC, Zakaria SK, Matusop A, Julin RA, Conway DJ, Cox-Singh J, Singh B | year = 2011 | title = Plasmodium knowlesi: Reservoir Hosts and Tracking the Emergence in Humans and Macaques | journal = PLOS Pathog | volume = 7 | issue = 4| page = e1002015| pmid=21490952 | doi = 10.1371/journal.ppat.1002015 | pmc = 3072369 | editor1-last = Kazura | editor1-first = James W. | doi-access = free }}</ref> Among human parasites, ''P. knowlesi'' is most closely related to ''P. vivax'', from which it diverged between 18 million and 34 million years ago.<ref name=Garrido2018/><ref name=Pasini2016>{{cite journal|title=''Plasmodium knowlesi'': a relevant, versatile experimental malaria model |date=November 2016 |vauthors=Pasini EM, Zeeman AM, Voorberg-Vanderwel A, Kocken CH |journal=Parasitology |volume=145 |issue=1 |pages=56–70 |publisher=Cambridge University Press |doi=10.1017/S0031182016002286|pmid=27938428 |s2cid=9261727 }}</ref> A [[phylogenetic tree]] comparing the ''Plasmodium'' species that infect humans is shown below:<ref name=Garrido2018/>
{{clade| style=font-size:85%;line-height:85%
|1=''[[Plasmodium falciparum|P. falciparum]]'' 
|label2=Subgenus ''Plasmodium''
|2={{clade
    |1=''[[Plasmodium malariae|P. malariae]]''
    |2= {{clade
        |1=''[[Plasmodium ovale|P. ovale]]''
        |2= {{clade
            |1=''[[Plasmodium vivax|P. vivax]]''
            |2=''P. knowlesi''
            }}
        }}
    }} 
}}

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.<ref name=Garrido2018/> Two are present in the same areas of Malaysian Borneo and may infect different mosquitoes.<ref name=Garrido2018/> The third has been found only in laboratory isolates originating from other parts of Southeast Asia.<ref name=Garrido2018/> Populations of ''P. knowlesi'' isolated from macaques are genetically indistinguishable from those isolated from human infections, suggesting the same parasite populations can infect humans and macaques interchangeably.<ref name=Millar2015/>

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.<ref name=Butcher2016>{{cite journal|title=The role of ''Plasmodium knowlesi'' in the history of malaria research |vauthors=Butcher GA, Mitchell GH |date=September 2016 |journal=Parasitology |volume=145 |issue=1 |publisher=Cambridge University Press |doi=10.1017/S0031182016001888 |pmid=27829470 |pages=6–17|s2cid=13209647 }}</ref><ref name="Garnham1963">{{cite journal| author=Garnham PC| title=A new sub-species of Plasmodium knowlesi in the long-tailed macaque. | journal=J Trop Med Hyg | year= 1963 | volume= 66 | pages= 156–8 | pmid=13960457 | url=https://pubmed.ncbi.nlm.nih.gov/13960457  }}</ref> The relationship between these described subspecies and the populations described in the modern literature is not clear.<ref name=Butcher2016/>

==Distribution==
''Plasmodium knowlesi'' is found throughout [[Southeast Asia]], where it primarily infects the [[Macaca fascicularis|long-tailed macaque]], [[Macaca nemestrina|pig-tailed macaque]], and [[Presbytis melalophos|Sumatran surili]] as well as the mosquito vectors ''[[Anopheles hackeri]]'' in peninsular Malaysia and ''[[Anopheles latens]]'' in [[Sarawak]].<ref name=Collins2012/> Long-tailed macaques in the wild can be infected with ''P. knowlesi'' <ref name="Yusuf2022">{{cite journal | last1=Yusuf | first1=Noorazian Md | last2=Zulkefli | first2=Jannah | last3=Jiram | first3=Adela Ida | last4=Vythilingam | first4=Indra | last5=Hisam | first5=Shamilah | last6=Devi | first6=Renuka | last7=Salehhuddin | first7=Afiqah | last8=Ali | first8=Nurulshuhada Md | last9=Isa | first9=Maccallyster | last10=Alias | first10=Norwahida | last11=Ogu salim | first11=Nurhainis | last12=Aziz | first12=Adli Abd | last13=Sulaiman | first13=Lokman Hakim | title=''Plasmodium'' spp. in macaques, ''Macaca fascicularis'', in Malaysia, and their potential role in zoonotic malaria transmission | journal=Parasite | publisher=EDP Sciences | volume=29 | year=2022 | issn=1776-1042 | doi=10.1051/parasite/2022032 | page=32| pmid=35674419 | pmc=9175634 }}</ref> without any apparent disease, even when they are simultaneously infected with various other ''Plasmodium'' species.<ref name=Butcher2016/><ref name=Pasini2016/> ''P. knowlesi'' is rarely found outside of Southeast Asia, likely because the mosquitoes it infects are restricted to that region.<ref name=Millar2015/>

==Role in human disease==
[[File:P knowlesi smears.png|thumb|upright=1.2|Giemsa-stained thin blood smears of human red blood cells infected with ''Plasmodium knowlesi'']]
''P. knowlesi'' can cause both [[Malaria#Classification|uncomplicated]] and [[Malaria#Classification|severe]] malaria in humans. Those infected nearly always experience [[fever]] and [[chills]].<ref name=Singh2013>{{cite journal|doi=10.1128/CMR.00079-12|pmid=23554413|pmc=3623376|title=Human Infections and Detection of Plasmodium knowlesi|journal=Clinical Microbiology Reviews|volume=26|issue=2|pages=165–184|year=2013|vauthors=Singh B, Daneshvar C}}</ref> People with uncomplicated ''P. knowlesi'' malaria often also experience headaches, joint pain, [[malaise]], and loss of appetite.<ref name=Singh2013/> Less commonly, people report coughing, abdominal pain, diarrhea, nausea, and vomiting.<ref name=Singh2013/> Laboratory tests of infected people nearly always show a [[thrombocytopenia|low platelet count]], although this rarely leads to bleeding problems.<ref name=Singh2013/> Unlike other human malarias, ''P. knowlesi'' malaria tends to have fevers that spike every 24 hours, and is therefore often called daily or "quotidian" malaria.<ref name="Singh2013"/><ref name=Chin>{{cite journal |vauthors=Chin W, Contacos PG, Coatney RG, Kimbal HR | journal=Science | year=1965 | title=A naturally acquired quotidian-type malaria in man transferable to monkeys | volume=149 | pages=865 | pmid=14332847 | doi=10.1126/science.149.3686.865 | issue=3686| bibcode=1965Sci...149..865C | s2cid=27841173 }}</ref> Uncomplicated ''P. knowlesi'' malaria can be treated with [[antimalarial drugs]] such as artemisinin combination therapy (ACT) or chloroquine<ref name=Singh2013/><ref>{{Citation |last1=Barber |first1=Bridget E. |title=Clinical management of Plasmodium knowlesi malaria |date=2021 |journal=Advances in Parasitology |volume=113 |pages=45–76 |publisher=Elsevier |language=en |doi=10.1016/bs.apar.2021.08.004 |isbn=978-0-323-90727-9 |pmc=9299581 |pmid=34620385 |last2=Grigg |first2=Matthew J. |last3=Cooper |first3=Daniel J. |last4=van Schalkwyk |first4=Donelly A. |last5=William |first5=Timothy |last6=Rajahram |first6=Giri S. |last7=Anstey |first7=Nicholas M.}}</ref> ACT is the preferred treatment as the drug is associated with a faster parasite clearance time. 

At least 10% of people infected with ''P. knowlesi'' develop severe malaria.<ref name=Millar2015>{{cite journal|title=Human infections with ''Plasmodium knowlesi''-zoonotic malaria |journal=Clinical Microbiology and Infection |publisher=Elsevier |volume=21 |issue=7 |date=July 2015 |pages=640–648 |doi=10.1016/j.cmi.2015.03.017 |pmid=25843504 |vauthors=Millar SB, Cox-Singh J|doi-access=free }}</ref> Severe ''P. knowlesi'' malaria resembles severe malaria caused by ''P. falciparum''. Those with severe disease may experience shortness of breath, abdominal pain, and vomiting.<ref name=Singh2013/> As disease progresses, parasites replicate to [[hyperparasitemia|very high levels]] in the blood likely causing acute kidney injury, [[jaundice]], shock, and respiratory distress.<ref name=Singh2013/><ref name=Barber2017/> [[Metabolic acidosis]] is uncommon, but can occur in particularly severe cases.<ref name=Barber2017/>  Unlike ''P. falciparum'' malaria, severe ''P. knowlesi'' malaria rarely causes [[coma]] or severe [[anemia]].<ref name=Singh2013/><ref name=Barber2017/> Approximately 1-2% of cases are fatal.<ref name=Millar2015/>

===Diagnosis===
Malaria is traditionally diagnosed by examining [[Giemsa|Giemsa-stained]] blood films under a microscope; however, differentiating ''P. knowlesi'' from other ''Plasmodium'' species in this way is challenging due to their similar appearance.<ref name=Millar2015/> ''P. knowlesi'' ring-stage parasites stained with Giemsa resemble ''P. falciparum'' ring stages, appearing as a circle with one or two dark dots of [[chromatin]].<ref name=CDCdiag>{{cite web|url=https://www.cdc.gov/dpdx/malaria/index.html |access-date=20 January 2020 |title=DPDx Malaria - Image Gallery |publisher=U.S. Centers for Disease Control and Prevention |date=29 December 2017}}</ref>  Older trophozoites appear more dispersed, forming a rectangular-shape spread across the host cell called a "band-form" that resembles the similar stage in ''P. malariae''.<ref name=CDCdiag/> During this stage, dots sometimes appear across the host red blood cell, called "Sinton and Mulligans' stippling".<ref name=CDCdiag/> Schizonts appear, similarly to other ''Plasmodium'' species, as clusters of purple merozoites surrounding a central dark-colored pigment.<ref name=CDCdiag/>

Due to the morphological similarity among ''Plasmodium'' species, misdiagnosis of ''P. knowlesi'' infection as ''P. falciparum'', ''P. malariae'', or ''P. vivax'' is common.<ref name=Barber2017>{{cite journal|title=The treatment of ''Plasmodium knowlesi'' malaria |journal=Trends in Parasitology |publisher=Elsevier |volume=33 |issue=3 |date=March 2017 |pages=242–253 |vauthors=Barber BE, Grigg MJ, William T, Yeo TW, Anstey NM |doi=10.1016/j.pt.2016.09.002|pmid=27707609 }}</ref> While some [[Malaria antigen detection tests|rapid diagnostic test]]s can detect ''P. knowlesi'', they tend to have poor [[sensitivity and specificity]] and are therefore not always reliable.<ref name=Barber2017/><ref name=PD7>{{cite book|title=Parasitic Diseases |edition=7 |page=112 |vauthors=Despommier DD, Griffin DO, Gwadz RW, Hotez PJ, Knirsch CA |publisher=Parasites Without Borders |url=https://s3.amazonaws.com/parasiteswithoutborders/PD+7th+Edition+Low+Res+Version+5-11-2019.pdf}}</ref> Detection of [[nucleic acid]] by [[Polymerase chain reaction|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.<ref name=Millar2015/> [[Loop-mediated isothermal amplification]] methods of ''P. knowlesi'' detection have also been developed, but are not yet widely used.<ref name=Millar2015/>

===Treatment===
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.<ref name=Barber2017/> For those with [[Malaria#Classification|uncomplicated malaria]], the [[World Health Organization]] recommends treatment with [[artemisinin-based combination therapy]] (ACT) or [[chloroquine]].<ref>{{cite book|page=60 |chapter=Treatment of uncomplicated malaria caused by ''P. vivax'', ''P. ovale'', ''P. malariae'', or ''P. knowlesi'' |title=Guidelines for the Treatment of Malaria |edition=3 |publisher=World Health Organization |url=https://www.who.int/malaria/publications/atoz/9789241549127/en/ |archive-url=https://web.archive.org/web/20150425070556/http://www.who.int/malaria/publications/atoz/9789241549127/en/ |url-status=dead |archive-date=April 25, 2015 |access-date=22 January 2020 |date=2015 |isbn=978-92-4-154912-7}}</ref> For those with [[Malaria#Classification|severe malaria]], the World Health Organization recommends administration of intravenous [[artesunate]] for at least 24 hours, followed by ACT treatment.<ref name=Barber2017/> Additionally, early drug trials have suggested that combinations of chloroquine and [[primaquine]], artesunate and [[mefloquine]], [[artemether]] and [[lumefantrine]], and chloroquine alone could be effective treatments for uncomplicated ''P. knowlesi'' malaria.<ref name=Barber2017/> There is no evidence of ''P. knowlesi'' developing resistance to current antimalarials.<ref name=Barber2017/>

===Epidemiology===
''P. knowlesi'' is the most common cause of malaria in [[Malaysia]],<ref name=Garrido2018>{{cite journal|title=''Plasmodium'' genomics: an approach for learning about and ending human malaria |journal=Parasitology Research |publisher=Springer |date=January 2019 |volume=118 |issue=1 |pages=1–27 |vauthors=Garrido-Cardenas JA, Gonzalez-Ceron L, Manzano-Agugliaro F, Mesa-Valle C |doi=10.1007/s00436-018-6127-9|pmid=30402656 |s2cid=53228888 |doi-access=free }}</ref> and cases of ''P. knowlesi'' malaria have been reported in most countries of Southeast Asia as well as travelers from the region.<ref name=Millar2015/>

Infection with ''P. knowlesi'' is associated with socioeconomic and lifestyle factors that bring people into the dense forests where the mosquito hosts are commonly found.<ref name=Singh2013/> In particular, those who work in the forest or at its margin such as farmers, hunters, and loggers are at increased risk for infection.<ref name=Singh2013/> Likely for this reason, males are infected more frequently than females, and adults are infected more frequently than children.<ref name=Singh2013/>

==Research==
''P. knowlesi'' has long been used as a research model for studying the interaction between parasite and host, and developing antimalarial vaccines and drugs.<ref name=Pasini2016/> Its utility as a research model is partly due to its ability to infect rhesus macaques, a common laboratory model primate. Rhesus macaques are highly susceptible to ''P. knowlesi'' and can be infected by mosquito bite, injection of sporozoites, or injection of blood-stage parasites.<ref name=Butcher2016/><ref name=Pasini2016/> Infected monkeys develop some hallmarks of human malaria including anemia and enlargement of the spleen and liver.<ref name=Butcher2016/> Infection is typically fatal if untreated, with the cause of death seemingly [[circulatory system|circulatory]] failure characterized by adhesion of infected red blood cells to the [[blood vessel]] walls.<ref name=Butcher2016/> Monkeys can be cured of infection by treatment with antimalarials; repeated infection followed by cure results in the monkeys developing some immunity to infection, a topic that has also been the subject of substantial research.<ref name=Butcher2016/>

''P. knowlesi'' is also used for ''[[in vitro]]'' research into ''Plasmodium'' cell biology. Isolated sporozoites can infect [[primary cell|primary]] rhesus [[hepatocyte]]s, allowing the ''in vitro'' study of the parasite liver stage.<ref name=Pasini2016/> Additionally, ''P. knowlesi'' and ''P. falciparum'' are the only ''Plasmodium'' species that can be maintained continuously in [[cell culture|cultured]] red blood cells, both rhesus and human.<ref name=Pasini2016/> Facilitating molecular biology research, the ''P. knowlesi'' genome has been sequenced and is available on [[PlasmoDB]] and other online repositories.<ref name=Pasini2016/> ''P. knowlesi'' can be genetically modified in the lab by [[transfection]] either in the rhesus macaque model system, or in blood cell culture.<ref name=Pasini2016/><ref>{{cite journal|title=Advances in molecular genetic systems in malaria |author1=de Koning-Ward TF |author2=Gilson PR |author3=Crabb BS |journal=Nature Reviews Microbiology |publisher=Macmillan |volume=13 |issue=6 |pages=373–387 |date=June 2015 |doi=10.1038/nrmicro3450|pmid=25978707 |s2cid=19786233 }}</ref> Blood-infecting stages and sporozoites can be stored long-term by freezing with [[glycerolyte]], allowing the preservation of strains of interest.<ref name=Collins2012/>

==History==
[[File:Robert Knowles. Photograph by Edna Lorenz, Calcutta. Wellcome V0027741.jpg|thumb|Robert Knowles, after whom ''P. knowlesi'' was named]]
The Italian physician [[Giuseppe Franchini]] first described what may have been ''P. knowlesi'' in 1927 when he noted a parasite distinct from ''[[Plasmodium cynomolgi|P. cynomolgi]]'' and ''[[Plasmodium inui|P. inui]]'' in the blood of a long-tailed macaque.<ref name=Franchini1927>Franchini G (1927) Su di un plasmodio pigmentato di una scimmia. Arch Ital Sci Med Colon 8:187–90</ref><ref>{{cite journal|title=''Plasmodium knowlesi'': an overlooked Italian discovery? |vauthors=Antinori S, Milazzo L, Corbellino M |journal=Clinical Infectious Diseases |doi=10.1093/cid/cir527 |pmid=21890752 |volume=53 |issue=8 |pages=849; author reply 849–50 |date=October 2011 |doi-access=free }}</ref> In 1931, the parasite was again seen in a long-tailed macaque by H. G. M. Campbell during his work on ''kala azar'' ([[visceral leishmaniasis]]) in [[Calcutta]]; Campbell's colleague [[Lionel Everard Napier]] drew blood from the affected monkey and [[Inoculation|inoculated]] three laboratory monkeys, one of which was a rhesus macaque that developed a severe infection.<ref name=Coatney>{{cite book|title=The Primate Malarias |date=1971 |vauthors=Coatney GR, Collins WE, Warren M, Contacos PG |publisher=Division of Parasitic Diseases, U.S. Centers for Disease Control |location=Atlanta, GA |url=https://stacks.cdc.gov/view/cdc/6538 |access-date=26 August 2019 |pages=317–334}}</ref><ref>{{cite journal|url=http://pdfs.semanticscholar.org/8cad/758a4a40a3f5802e264e4abc059d9a9eb775.pdf |archive-url=https://web.archive.org/web/20190228133808/http://pdfs.semanticscholar.org/8cad/758a4a40a3f5802e264e4abc059d9a9eb775.pdf |url-status=dead |archive-date=2019-02-28 |access-date=27 August 2019 |title=Observations on a Plasmodium infection which causes haemoglobinuria in certain species of monkey |author1=Napier LE |author2=Campbell HGM |date=May 1932 |pages=246–249 |journal=The Indian Medical Gazette|s2cid=26553543 }}</ref> Campbell and Napier gave the infected monkey to [[Biraj Mohan Das Gupta]] who was able to maintain the parasite by serial passage through monkeys.<ref name=Antinori2013>{{cite journal|doi=10.1016/j.actatropica.2012.10.008|pmid=23088834|title=Plasmodium knowlesi: The emerging zoonotic malaria parasite|journal=Acta Tropica|volume=125|issue=2|pages=191–201|year=2013|vauthors=Spinello A, Galimberti L, Milaazo L, Corbellino M|doi-access=free}}</ref> In 1932, Das Gupta and his supervisor [[Robert Knowles (parasitologist)|Robert Knowles]] described the morphology of the parasite in macaque blood, and demonstrated that it could infect three human patients (in each case it was used to induce fever with the hope of treating another infection).<ref name=Coatney/><ref>{{cite journal|title=A study of monkey malaria, and its experimental transmission to man |vauthors=Knowles R, Das Gupta BM |journal=Indian Medical Gazette |date=June 1932 |volume=67 |issue=6 |pages=301–320 |pmc=5231565|pmid=29010910 }}</ref> Also in 1932, [[John Alexander Sinton|John Sinton]] and H. W. Mulligan further described the morphology of the parasite in blood cells, determined it to be a distinct species from others described, and named it ''Plasmodium knowlesi'' in honor of Robert Knowles.<ref name=Coatney/>

Soon thereafter, in 1935 C. E. Van Rooyen and George R. Pile reported using ''P. knowlesi'' infection to treat [[general paralysis of the insane|general paralysis]] in psychiatric patients. ''P. knowlesi'' would go on to be used as a general [[fever|pyretic agent]] for various diseases, particularly [[neurosyphilis]] for which it was used until at least 1955.<ref name=Antinori2013/> While [[Cyril Garnham]] had suggested in 1957 that ''P. knowlesi'' might naturally infect humans,<ref name="Garnham1957">{{cite journal |vauthors=Garnham PC, Lainson R, Cooper W |year=1957 |title= The tissue stages and sporogony of ''Plasmodium knowlesi'' | journal = Trans R Soc Trop Med Hyg |volume= 51 |issue=5 |pages=384–396 | doi=10.1016/0035-9203(57)90071-8 | pmid=13467997 }}</ref> the first documented case of a human naturally infected with ''P. knowlesi'' was in 1965 in a U.S. Army surveyor who developed chills and fever after a five-day deployment in Malaysia.<ref name=Antinori2013/><ref name="ReferenceA">{{cite journal|last1=Mason Dentinger|first1=R|title=Patterns of Infection and Patterns of Evolution: How a Malaria Parasite Brought "Monkeys and Man" Closer Together in the 1960s|journal=Journal of the History of Biology|date=26 August 2015|volume=49|issue=2|pages=359–395|doi=10.1007/s10739-015-9421-8|pmid=26307748|doi-access=free}}</ref> Based on this finding, a team at the Institute for Medical Research in Peninsular Malaysia undertook a survey of people living in proximity to macaques, but failed to find evidence that simian malaria was being transmitted to humans.<ref name=Antinori2013/>

Through the 1960s and 1970s, scientific research groups used ''P. knowlesi'' as a research model to make seminal discoveries in malaria. In 1965 and 1972, several groups characterized how ''P. knowlesi'' [[antigenic variation]] contributed to immune evasion and chronic infection.<ref name=Antinori2013/> In 1975, [[Louis H. Miller]] and others showed that ''P. knowlesi'' required [[Duffy antigen system|Duffy factor]] on the surface of red blood cells in order to invade them (they would go on to show the same requirement for ''P. vivax'' a year later).<ref name=Antinori2013/>

Work on ''P. knowlesi'' as a human malaria parasite was revitalized in 2004, when [[Balbir Singh (scientist)|Balbir Singh]] and others used [[Polymerase chain reaction|PCR]] to show that over half of a group of humans diagnosed with ''P. malariae'' malaria in Malaysian Borneo were actually infected with ''P. knowlesi''.<ref name=Antinori2013/><ref name=Singh2004>{{cite journal | journal=Lancet | year=2004 | volume=363 | issue=9414 | pages=1017–24 | title=A large focus of naturally acquired ''Plasmodium knowlesi'' infections in human beings |vauthors=Singh B, Lee KS, Matusop A, Radhakrishnan A, Shamsul SS, Cox-Singh J, Thomas A, Conway DJ | doi=10.1016/S0140-6736(04)15836-4 | pmid=15051281 | s2cid=7776536 | url=http://ir.unimas.my/2202/1/A%20large%20focus%20of%20naturally%20acquired%20Plasmodium%20knowlesi%20infections%20in%20human%20beings.pdf }}</ref> Over the following decade, several investigators used molecular detection methods capable of distinguishing ''P. knowlesi'' from morphologically similar parasites to attribute an increasing proportion of malaria cases to ''P. knowlesi'' throughout Southeast Asia.<ref name=Vythilingam2008>{{cite journal |vauthors=Vythilingam I, Noorazian YM, Huat TC, Jiram AI, Yusri YM, Azahari AH, Norparina I, Noorrain A, Lokmanhakim S |year=2008|title=Plasmodium knowlesi in humans, macaques and mosquitoes in peninsular Malaysia | journal=Parasit Vectors|volume=1|issue=1 |page= 26 | pmid= 18710577 |doi=10.1186/1756-3305-1-26 | pmc = 2531168 |doi-access=free }}</ref> Work with archival samples has shown that infection with this parasite has occurred in Malaysia at least since the 1990s.<ref name=Lee>{{cite journal |author1=Lee KS |author2=Cox-Singh J |author3=Brooke G |author4=Matusop A |author5=Singh B |year=2009 |title = Plasmodium knowlesi from archival blood films: Further evidence that human infections are widely distributed and not newly emergent in Malaysian Borneo | journal = Int J Parasitol | doi=10.1016/j.ijpara.2009.03.003 | volume = 39 | issue = 10 | pages = 1125–1128 | pmid = 19358848 | pmc = 2722692}}</ref>

== References ==
{{Reflist|2}}

==External links==
*[https://www.cdc.gov/EID/content/14/11/1750.htm CDC malaria page]
*[https://www.who.int/topics/malaria/en/ WHO malaria page]
*[https://web.archive.org/web/20091005030751/http://www.genedb.org/genedb/pknowlesi/ P. knowlesi genome data]
*[http://www.abc.net.au/catalyst/stories/2533454.htm Short film on the discovery of the role of ''P. knowlesi'' in human malaria]
{{Scholia|topic}}

{{malaria}}
{{Chromalveolate diseases}}

{{Taxonbar|from=Q241594}}

{{DEFAULTSORT:Plasmodium Knowlesi}}
[[Category:Plasmodium|knowlesi]]
[[Category:Parasites of primates]]