Editing Plasmodium

{{Short description|Genus of parasitic protists that can cause malaria}}
{{For|the multinucleate stage of some microorganisms|Plasmodium (life cycle)}}
{{Good article}}
{{Automatic taxobox
| image = Malaria.jpg
| image_alt = False-colored electron micrograph of a sporozoite
| image_caption = False-colored [[electron micrograph]] of a [[sporozoite]]
| taxon = Plasmodium
| authority = [[Ettore Marchiafava|Marchiafava]] & [[Angelo Celli|Celli]], 1885
| synonyms_ref = <!--
| subdivision_ranks = Subgenera and species
| subdivision_ref = <ref>{{cite web|title=''Plasmodium''|url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Undef&id=5820&lvl=3&srchmode=1&keep=1&unlock|website=NCBI taxonomy|publisher=National Center for Biotechnology Information|access-date=5 January 2019|location=Bethesda, MD|language=en|format=HTML}}</ref>
| subdivision = 
* ''[[Bennettinia|Plasmodium (Bennettinia)]]''
* ''[[Carinamoeba|Plasmodium (Carinamoeba)]]''
** ''[[Plasmodium carmelinoi]]''
* ''[[Giovannolaia|Plasmodium (Giovannolaia)]]''
** ''[[Plasmodium circumflexum]]''
** ''[[Plasmodium homocircumflexum]]''
** ''[[Plasmodium lophurae]]''
** ''[[Plasmodium polare]]''
* ''[[Haemamoeba|Plasmodium (Haemamoeba)]]''
** ''[[Plasmodium cathemerium]]''
** ''[[Plasmodium gallinaceum]]''
** ''[[Plasmodium lutzi]]''
** ''[[Plasmodium matutinum]]''
** ''[[Plasmodium relictum]]''
** ''[[Plasmodium tejerai]]''
* ''[[Huffia|Plasmodium (Huffia)]]''
** ''[[Plasmodium elongatum]]''
* ''[[Lacertamoeba|Plasmodium (Lacertamoeba)]]''
** ''[[Plasmodium floridense]]''
* ''[[Laverania|Plasmodium (Laverania)]]''
** ''[[Plasmodium billbrayi]]''
** ''[[Plasmodium falciparum]]''
** ''[[Plasmodium gaboni]]''
** ''[[Plasmodium lomamiensis]]''
** ''[[Plasmodium reichenowi]]''
* ''[[Novyella|Plasmodium (Novyella)]]''
** ''[[Plasmodium ashfordi]]''
** ''[[Plasmodium delichoni]]''
** ''[[Plasmodium globularis]]''
** ''[[Plasmodium homonucleophilum]]''
** ''[[Plasmodium homopolare]]''
** ''[[Plasmodium juxtanucleare]]''
** ''[[Plasmodium lucens]]''
** ''[[Plasmodium megaglobularis]]''
** ''[[Plasmodium multivacuolaris]]''
** ''[[Plasmodium nucleophilum]]''
** ''[[Plasmodium parahexamerium]]''
** ''[[Plasmodium paranucleophilum]]''
** ''[[Plasmodium rouxi]]''
** ''[[Plasmodium unalis]]''
** ''[[Plasmodium vaughani]]''
* ''[[Paraplasmodium|Plasmodium (Paraplasmodium)]]''
** ''[[Plasmodium chiricahuae]]''
** ''[[Plasmodium mexicanum]]''
* ''[[Plasmodium (Plasmodium)|Plasmodium (Plasmodium)]]''
** ''[[Plasmodium brasilianum]]''
** ''[[Plasmodium cynomolgi]]''
** ''[[Plasmodium cynomolgi bastianelli]]''
** ''[[Plasmodium cynomolgi ceylonensis]]''
** ''[[Plasmodium fieldi]]''
** ''[[Plasmodium fragile]]''
** ''[[Plasmodium gonderi]]''
** ''[[Plasmodium inui]]''
** ''[[Plasmodium inui inui]]''
** ''[[Plasmodium knowlesi]]''
** ''[[Plasmodium malariae]]''
** ''[[Plasmodium ovale]]''
** ''[[Plasmodium ovale curtisi]]''
** ''[[Plasmodium ovale wallikeri]]''
** ''[[Plasmodium simiovale]]''
** ''[[Plasmodium vivax]]''
* ''[[Sauramoeba|Plasmodium (Sauramoeba)]]''
** ''[[Plasmodium agamae]]''
** ''[[Plasmodium giganteum]]''
** ''[[Plasmodium kentropyxi]]''
* ''[[Vinckeia|Plasmodium (Vinckeia)]]''
** ''[[Plasmodium atheruri]]''
** ''[[Plasmodium berghei]]''
** ''[[Plasmodium berghei ANKA]]''
** ''[[Plasmodium berghei yoelii]]''
** ''[[Plasmodium chabaudi]]''
** ''[[Plasmodium chabaudi adami]]''
** ''[[Plasmodium chabaudi chabaudi]]''
** ''[[Plasmodium vinckei]]''
** ''[[Plasmodium vinckei brucechwatti]]''
** ''[[Plasmodium vinckei lentum]]''
** ''[[Plasmodium vinckei petteri]]''
** ''[[Plasmodium vinckei vinckei]]''
** ''[[Plasmodium yoelii]]''
** ''[[Plasmodium yoelii killicki]]''
** ''[[Plasmodium yoelii nigeriensis]]''
** ''[[Plasmodium yoelii YM]]''
** ''[[Plasmodium yoelii yoelii]]''
*Species ''[[incertae sedis]]''
** ''[[Plasmodium azurophilum]]''
** ''[[Plasmodium bubalis]]''
** ''[[Plasmodium coatneyi]]''
** ''[[Plasmodium cuculus]]''
** ''[[Plasmodium cyclopsi]]''
** ''[[Plasmodium fairchildi]]''
** ''[[Plasmodium gemini]]''
** ''[[Plasmodium guanggong]]''
** ''[[Plasmodium heteronucleare]]''
** ''[[Plasmodium hispaniolae]]''
** ''[[Plasmodium hylobati]]''
** ''[[Plasmodium intabazwe]]''
** ''[[Plasmodium koreafense]]''
** ''[[Plasmodium lacertiliae]]''
** ''[[Plasmodium leucocytica]]''
** ''[[Plasmodium mackerrasae]]''
** ''[[Plasmodium megalotrypa]]''
** ''[[Plasmodium minuoviride]]''
** ''[[Plasmodium odocoilei]]''
** ''[[Plasmodium simium]]''
** ''[[Plasmodium streptopelia]]''
** ''[[Plasmodium zonuriae]]'' -->
}}

'''''Plasmodium''''' is a [[genus]] of unicellular [[eukaryote]]s that are [[obligate parasite]]s of [[vertebrate]]s and [[insect]]s. The life cycles of ''Plasmodium'' species involve development in a [[Hematophagy|blood-feeding]] insect [[host (biology)|host]] which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue (often the liver) before entering the bloodstream to infect [[red blood cell]]s. The ensuing destruction of host red blood cells can result in [[malaria]]. During this infection, some parasites are picked up by a blood-feeding insect ([[mosquito]]es in majority cases), continuing the life cycle.<ref name=CDCAbout>{{cite web |title=CDC – Malaria Parasites – About |url=https://www.cdc.gov/malaria/about/biology/parasites.html |website=CDC: Malaria |publisher=U.S. Centers for Disease Control and Prevention |access-date=28 December 2015}}</ref>

''Plasmodium'' is a member of the phylum [[Apicomplexa]], a large group of parasitic eukaryotes. Within Apicomplexa, ''Plasmodium'' is in the order [[Haemosporida]] and family [[Plasmodiidae]]. Over 200 species of ''Plasmodium'' have been described, many of which have been subdivided into 14 subgenera based on parasite morphology and host range. Evolutionary relationships among different ''Plasmodium'' species do not always follow taxonomic boundaries; some species that are morphologically similar or infect the same host turn out to be distantly related.

Species of ''Plasmodium'' are distributed globally wherever suitable hosts are found. Insect hosts are most frequently [[mosquito]]es of the genera ''[[Culex]]'' and ''[[Anopheles]]''. Vertebrate hosts include reptiles, birds, and mammals. ''Plasmodium'' parasites were first identified in the late 19th century by [[Charles Laveran]]. Over the course of the 20th century, many other species were discovered in various hosts and classified, including five species that regularly infect humans: ''[[Plasmodium vivax|P. vivax]]'', ''[[Plasmodium falciparum|P. falciparum]]'', ''[[Plasmodium malariae|P. malariae]]'', ''[[Plasmodium ovale|P. ovale]]'', and ''[[Plasmodium knowlesi|P. knowlesi]]''. ''P. falciparum'' is by far the most lethal in humans, resulting in hundreds of thousands of deaths per year. A number of [[antimalarial medication|drugs]] have been developed to treat ''Plasmodium'' infection; however, the parasites have evolved resistance to each drug developed.

Although the parasite can also infect people via [[blood transfusion]], this is very rare, and ''Plasmodium'' cannot be spread from person to person. Some of subspecies of ''Plasmodium'' are [[Intracellular parasite|obligate intracellular parasites]].

== Description ==
[[File:Plasmodium.png|thumb|''Plasmodium'' is a [[eukaryote]] but with unusual features.]]

The genus ''Plasmodium'' consists of all [[eukaryote]]s in the phylum Apicomplexa that both undergo the asexual replication process of [[merogony]] inside host [[red blood cell]]s and produce the crystalline pigment [[hemozoin]] as a byproduct of digesting host [[hemoglobin]].<ref name=TOL/> ''Plasmodium'' species contain many features that are common to other eukaryotes, and some that are unique to their phylum or genus. The ''Plasmodium'' [[genome]] is separated into 14 [[chromosomes]] contained in the [[cell nucleus|nucleus]]. ''Plasmodium'' parasites maintain [[haploid|a single copy]] of their genome through much of the life cycle, [[diploid|doubling]] the genome only for a brief sexual exchange within the [[midgut]] of the insect host.<ref name=Obado>{{cite journal|doi=10.1016/j.molbiopara.2016.07.008|pmid=27475118|title=The nuclear envelope and gene organization in parasitic protozoa: Specializations associated with disease|journal=Molecular and Biochemical Parasitology|volume=209|issue=1–2|pages=104–113|year=2016|last1=Obado|first1=Samson O|last2=Glover|first2=Lucy |last3=Deitsch |first3=Kirk W.}}</ref> Attached to the nucleus is the [[endoplasmic reticulum]] (ER), which functions similarly to the ER in other eukaryotes. Proteins are trafficked from the ER to the [[Golgi apparatus]] which generally consists of a single membrane-bound compartment in Apicomplexans.<ref name=Ruiz>{{cite journal|doi= 10.1016/j.molbiopara.2016.01.007|pmid= 26844642|pmc= 5154328|title= Vacuolar protein sorting mechanisms in apicomplexan parasites|journal= Molecular and Biochemical Parasitology|volume= 209|issue= 1–2|pages= 18–25|year= 2016|last1= Jimenez-Ruiz|first1= Elena|last2= Morlon-Guyot|first2= Juliette|last3= Daher|first3= Wassim|last4= Meissner|first4= Markus}}</ref> From here, proteins are trafficked to various cellular compartments or to the cell surface.<ref name=Ruiz/>

Like other apicomplexans, ''Plasmodium'' species have several cellular structures at the [[Anatomical terms of location#apical|apical]] end of the parasite that serve as specialized organelles for secreting effectors into the host. The most prominent are the bulbous [[rhoptry|rhoptries]] which contain parasite proteins involved in invading the host cell and modifying the host once inside.<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> Adjacent to the rhoptries are smaller structures termed [[microneme]]s that contain parasite proteins required for motility as well as recognizing and attaching to host cells.<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> Spread throughout the parasite are secretory [[Vesicle (biology and chemistry)|vesicle]]s called [[dense granules]] that contain parasite proteins involved in modifying the membrane that separates the parasite from the host, termed the [[parasitophorous vacuole]].<ref name=Kemp2013/>

Species of ''Plasmodium'' also contain two large membrane-bound organelles of [[Symbiogenesis|endosymbiotic origin]], the [[mitochondria|mitochondrion]] and the [[apicoplast]], both of which play key roles in the parasite's [[metabolism]]. Unlike mammalian cells which contain many mitochondria, ''Plasmodium'' cells contain a single large mitochondrion that coordinates its division with that of the ''Plasmodium'' cell.<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> Like in other eukaryotes, the ''Plasmodium'' mitochondrion is capable of generating energy in the form of [[Adenosine triphosphate|ATP]] via the [[citric acid cycle]]; however, this function is only required for parasite survival in the insect host, and is not needed for growth in red blood cells.<ref name=Sheiner2013/> A second organelle, the apicoplast, is derived from a [[secondary endosymbiosis]] event, in this case the acquisition of a [[red alga]] by the ''Plasmodium'' ancestor.<ref name=McFadden2016>{{cite journal|doi=10.1016/j.ijpara.2016.08.005|pmid=27773518|title=The apicoplast: Now you see it, now you don't|journal=International Journal for Parasitology|volume=47|issue=2–3|pages=137–144 |year=2017|last1=McFadden|first1=Geoffrey Ian|last2=Yeh|first2=Ellen|pmc=5406208}}</ref> The apicoplast is involved in the synthesis of various metabolic precursors, including [[fatty acid]]s, [[isoprenoid]]s, [[iron-sulphur cluster]]s, and components of the [[heme]] biosynthesis pathway.<ref>{{cite journal|last1=Dooren|first1=Giel|last2=Striepen |first2=Boris |title=The Algal Past and Parasite Present of the Apicoplast|journal=Annual Review of Microbiology|date=June 26, 2013|volume=67|pages=271–289|doi=10.1146/annurev-micro-092412-155741|pmid=23808340}}</ref>

==Life cycle==
[[File:Life Cycle of the Malaria Parasite.jpg|thumb|right|Life cycle of a species that infects humans]]
[[File:Malarial parasites, Plasmodium species, ring forms in red blood cells.jpg|right|thumb|Ring forms of ''Plasmodium'' inside human red blood cells ([[Giemsa stain]])]]

The life cycle of ''Plasmodium'' involves several distinct stages in the insect and vertebrate [[Host (biology)|hosts]]. Parasites are generally introduced into a vertebrate host by the bite of an insect host (generally a mosquito, with the exception of some ''Plasmodium'' species of reptiles).<ref name=Sullivan>{{cite book|title=Malaria: Drugs, Disease, and Post-genomic Biology |date=2005 |editor1=Sullivan, D |editor2=Krishna, S.  |publisher=Springer |isbn=978-3-540-29088-9 |chapter=Molecular Genetics of Mosquito Resistance to Malaria Parasites |author1=Vernick, K.D. |author2=Oduol, F. |author3=Lazarro, B.P. |author4=Glazebrook, J. |author5=Xu, J. |author6=Riehle, M. |author7=Li, J. |page=384}}</ref> Parasites first infect the liver or other tissue, where they undergo a single large round of replication before exiting the host cell to infect [[red blood cell|erythrocytes]].<ref name=CDCBiology>{{cite web |title=CDC – Malaria Parasites – Biology|url=https://www.cdc.gov/malaria/about/biology/index.html |website=CDC: Malaria |publisher=U.S. Centers for Disease Control and Prevention |access-date=28 December 2015}}</ref> At this point, some species of ''Plasmodium'' of primates can form a long-lived dormant stage called a hypnozoite,<ref>{{cite journal | author=Markus, M. B. | title = Malaria: Origin of the Term 'Hypnozoite' | journal = Journal of the History of Biology | volume = 44 | issue = 4 | pages = 781–786 | date = 2011 | pmid = 20665090 | doi = 10.1007/s10739-010-9239-3| s2cid = 1727294 }}</ref> which can remain in the liver for more than a year.<ref>{{cite journal|doi=10.1101/cshperspect.a025486 |pmid=28242785 |title=Malaria Parasite Liver Infection and Exoerythrocytic Biology |journal=Cold Spring Harbor Perspectives in Medicine |volume=7 |issue=6 |pages=a025486 |year=2017 |last1=Vaughan |first1=Ashley M. |last2=Kappe |first2=Stefan H. I. |pmc=5453383 }}</ref> However, for most ''Plasmodium'' species, the parasites in infected liver cells are only what are called merozoites. After emerging from the liver, they enter red blood cells, as explained above. They then go through continuous cycles of erythrocyte infection, while a small percentage of parasites differentiate into a sexual stage called a gametocyte which is picked up by an insect host taking a blood meal. In some hosts, invasion of erythrocytes by ''Plasmodium'' species can result in disease, called malaria. This can sometimes be severe, rapidly followed by death of the host (e.g. ''P. falciparum'' in humans). In other hosts, ''Plasmodium'' infection can apparently be asymptomatic.<ref name=Sullivan/>

Even when humans have such subclinical plasmodial infections, there can nevertheless be very large numbers of multiplying parasites concealed in, particularly, the spleen and bone marrow. Certainly, this applies in the case of ''P. vivax''. These hidden parasites (in addition to hypnozoites) are thought to be the origin of instances of recurrent ''P. vivax'' malaria.<ref>{{cite journal |last1=Markus |first1=M. B. |title=Theoretical origin of genetically homologous Plasmodium vivax malarial recurrences |journal=Southern African Journal of Infectious Diseases |date=2022 |volume=37 |issue=1 |page=369 |doi=10.4102/sajid.v37i1.369 |pmid=35399558 |pmc=8991251}}</ref>

[[File:Malaria Sporozoites (16657642929).jpg|thumb|upright|[[Sporozoite]]s, one of several different forms of the parasite, from a mosquito]]

Within the red blood cells, the merozoites grow first to a ring-shaped form and then to a larger form called a [[trophozoite]]. Trophozoites then mature to [[schizont]]s which divide several times to produce new merozoites. The infected red blood cell eventually bursts, allowing the new merozoites to travel within the bloodstream to infect new red blood cells. Most merozoites continue this replicative cycle, however some merozoites upon infecting red blood cells differentiate into male or female sexual forms called gametocytes. These gametocytes circulate in the blood until they are taken up when a mosquito feeds on the infected vertebrate host, taking up blood which includes the gametocytes.<ref name=CDCBiology/>

In the mosquito, the gametocytes move along with the [[hematophagy|blood meal]] to the mosquito's midgut. Here the [[gametocyte]]s develop into male and female [[gamete]]s which [[fertilization|fertilize]] each other, forming a [[zygote]]. Zygotes then develop into a motile form called an [[ookinete]], which penetrates the wall of the midgut. Upon traversing the midgut wall, the ookinete embeds into the gut's exterior membrane and develops into an oocyst. Oocysts divide many times to produce large numbers of small elongated [[sporozoite]]s. These sporozoites migrate to the salivary glands of the mosquito where they can be injected into the blood of the next host the mosquito bites, repeating the cycle.<ref name=CDCBiology/>

==Evolution and taxonomy==
[[File:Culex malariager in Dominican amber.jpg|thumb|Oldest mosquito fossil with ''[[Plasmodium dominicana]]'', 15–20 million years old]]

=== Taxonomy ===
''Plasmodium'' belongs to the [[phylum]] [[Apicomplexa]], a taxonomic group of single-celled parasites with characteristic [[Apicomplexa#General features|secretory organelles]] at one end of the cell.<ref name=Morrison2009>{{cite journal |doi=10.1016/j.pt.2009.05.010 |pmid=19635681 |title=Evolution of the Apicomplexa: Where are we now? |journal=Trends in Parasitology |volume=25 |issue=8 |pages=375–82 |year=2009 |last1=Morrison |first1=David A.}}</ref> Within Apicomplexa, ''Plasmodium'' is within the [[Order (biology)|order]] [[Haemosporida]], a group that includes all apicomplexans that live within blood cells.<ref>{{cite web|url=http://tolweb.org/Haemosporina/124976 |access-date=1 May 2018 |title=Haemospororida Danielewski 1885 |author=Votypka J |website=Tree of Life}}</ref> Based on the presence of the pigment [[hemozoin]] and the method of [[Merogony|asexual reproduction]], the order is further split into four families, of which ''Plasmodium'' is in the [[Family (biology)|family]] [[Plasmodiidae]].<ref name=Perkins2014/>

The genus ''Plasmodium'' consists of over 200 species, generally described on the basis of their appearance in blood smears of infected vertebrates.<ref name=Martinsen2013>{{cite book |title=Malaria Parasites: Comparative Genomics, Evolution and Molecular Biology |editor1=Carlton, J.M. |editor2=Perkins, S.L. |editor3=Deitsch, K.W.  |isbn=978-1908230072 |publisher=Caister Academic Press |date=2013 |chapter=The Diversity of ''Plasmodium'' and other Haemosporidians: The Intersection of Taxonomy, Phylogenetics, and Genomics |author1=Martinsen, E. S. |author2=Perkins, S. L. |pages=1–15}}</ref> These species have been categorized on the basis of their morphology and host range into 14 subgenera:<ref name=Perkins2014>{{cite journal|title=Malaria's Many Mates: Past, Present, and Future of the Systematics of the Order Haemosporida |author=Perkins, S. L. |date=2014 |journal=Journal of Parasitology |volume=100 |issue=1 |pages=11–25 |doi=10.1645/13-362.1|pmid=24059436 |s2cid=21291855 }}</ref>

* Subgenus ''[[Asiamoeba]]'' <small>(Telford, 1988)</small> – reptiles
* Subgenus ''[[Bennettinia]]'' <small>(Valkiunas, 1997)</small> – birds
* Subgenus ''[[Carinamoeba]]'' <small>(Garnham, 1966)</small> – reptiles
* Subgenus ''[[Giovannolaia]]'' <small>(Corradetti, et al. 1963)</small> – birds
* Subgenus ''[[Haemamoeba]]'' <small>(Corradetti, et al. 1963)</small> – birds
* Subgenus ''[[Huffia]]'' <small>(Corradetti, et al. 1963)</small> – birds
* Subgenus ''[[Lacertamoeba]]'' <small>(Telford, 1988)</small> – reptiles
* Subgenus ''[[Laverania]]'' <small>(Bray, 1958)</small> – great apes, humans 
* Subgenus ''[[Novyella]]'' <small>(Corradetti, et al. 1963)</small> – birds
* Subgenus ''[[Ophidiella]]'' <small>(Telford, 1988)</small> – reptiles
* Subgenus ''[[Paraplasmodium]]'' <small>(Telford, 1988)</small> – reptiles
* Subgenus ''Plasmodium'' <small>(Bray, 1955)</small> – monkeys and apes
* Subgenus ''[[Sauramoeba]]'' <small>(Garnham, 1966)</small> – reptiles
* Subgenus ''[[Vinckeia]]'' <small>(Garnham, 1964)</small> – mammals inc. primates

Species infecting [[monkey]]s and [[apes]] with the exceptions of ''P. falciparum'' and ''P. reichenowi'' (which together make up the subgenus ''Laverania'') are classified in the subgenus ''Plasmodium''. Parasites infecting other [[mammal]]s including some primates ([[lemur]]s and others) are classified in the subgenus ''Vinckeia''. The five subgenera ''Bennettinia'', ''Giovannolaia'', ''Haemamoeba'', ''Huffia'', and ''Novyella'' contain the known avian malarial species.<ref name=Valkiunas4>{{cite book |title=Avian Malaria Parasites and Other Haemosporidia |author=Valkiunas, Gediminas  |publisher=CRC Press |isbn=9780415300971 |date=2004 |chapter=Brief Historical Summary |pages=9–15}}</ref> The remaining subgenera: ''Asiamoeba'', ''Carinamoeba'', ''Lacertamoeba'', ''Ophidiella'', ''Paraplasmodium'', and ''Sauramoeba'' contain the diverse groups of parasites found to infect reptiles.<ref name="Telford1988"/>

===Phylogeny===

More recent studies of ''Plasmodium'' species using molecular methods have implied that the group's evolution has not perfectly followed taxonomy.<ref name=TOL>{{cite web |url=http://tolweb.org/Plasmodium/68071 |access-date=1 June 2016 |title=''Plasmodium'' |publisher=Tree of Life Web Project |author1=Zilversmit, M. |author2=Perkins, S.}}</ref> Many ''Plasmodium'' species that are morphologically similar or infect the same hosts turn out to be only distantly related.<ref name=Rich2003>{{cite book |doi=10.1016/S0065-308X(03)54005-2 |pmid=14711087 |title=Progress in Malaria Research: the Case for Phylogenetics |volume=54 |pages=255–80 |year=2003 |last1=Rich |first1=S. |last2=Ayala |first2=F |series=Advances in Parasitology |isbn=978-0-12-031754-7}}</ref> In the 1990s, several studies sought to evaluate evolutionary relationships of ''Plasmodium'' species by comparing [[ribosomal RNA]] and a surface protein gene from various species, finding the human parasite ''P. falciparum'' to be more closely related to avian parasites than to other parasites of primates.<ref name=Perkins2014/> However, later studies sampling more ''Plasmodium'' species found the parasites of mammals to form a clade along with the genus ''[[Hepatocystis]]'', while the parasites of birds or lizards appear to form a separate clade with evolutionary relationships not following the subgenera:<ref name=Perkins2014/><ref>{{cite journal|doi=10.1016/j.ympev.2007.11.012 |pmid=18248741 |title=A three-genome phylogeny of malaria parasites (''Plasmodium'' and closely related genera): Evolution of life-history traits and host switches |vauthors=Martinsen ES, Perkins SL, Schall JJ |journal=Molecular Phylogenetics and Evolution |volume=47 |issue=1 |date=April 2008 |pages=261–273}}</ref>

{{clade| style=font-size:85%;line-height:85%
|1=''[[Leucocytozoon]]'' 
|2={{clade
    |1=''[[Haemoproteus]]''
    |label2=''Plasmodium''
    |2= {{clade
        |1=''Plasmodium'' of lizards and birds
        |2= {{clade
            |1=Subgenus ''Laverania''
            |2={{clade
                |1=Subgenus ''Plasmodium''
                |2=Subgenus ''Vinckeia''
                |3=''[[Hepatocystis]]'' (parasites of bats)
                }}
            }}
        }}
    }} 
}}

Estimates for when different ''Plasmodium'' lineages diverged have differed broadly. Estimates for the diversification of the order Haemosporida range from around 16.2 million to 100 million years ago.<ref name=Perkins2014/> There has been particular interest in dating the divergence of the human parasite ''P. falciparum'' from other ''Plasmodium'' lineages due to its medical importance. For this, estimated dates range from 110,000 to 2.5 million years ago.<ref name=Perkins2014/>

==Distribution==
''Plasmodium'' species are distributed globally. All ''Plasmodium'' species are parasitic and must pass between a vertebrate host and an insect host to complete their life cycles. Different species of ''Plasmodium'' display different host ranges, with some species restricted to a single vertebrate and insect host, while other species can infect several species of vertebrates and/or insects.

=== Vertebrates ===
[[File:Relative incidence of Plasmodium (malaria) species by country of origin for imported cases to non-endemic countries.png|thumb|Relative incidence of Plasmodium species by country of origin for imported cases to non-endemic countries<ref name="Tatem2017">{{Cite journal |author1=Tatem AJ |author2=Jia P |author3=Ordanovich D |author4=Falkner M |author5=Huang Z |author6=Howes R |author7=Hay S |author8=Gething, P W |author9=Smith, D L |display-authors=etal |title=The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics |journal=Lancet Infect Dis |year=2017 |volume=17 |issue=1 |pages=98–107 |pmid=27777030 |doi=10.1016/S1473-3099(16)30326-7 |pmc=5392593 }}</ref>]]

''Plasmodium'' parasites have been described in a broad array of vertebrate hosts including reptiles, birds, and mammals.<ref name=Manguin/> While many species can infect more than one vertebrate host, they are generally specific to one of these [[Class (biology)|classes]] (such as birds).<ref name=Manguin>{{cite book|title=Biodiversity of Malaria in the world |date=2008 |author1=Manguin, S. |author2=Carnevale, P. |author3=Mouchet, J. |author4=Coosemans, M. |author5=Julvez, J. |author6=Richard-Lenoble, D. |author7=Sircoulon, J. |publisher=John Libbey |isbn=978-2-7420-0616-8 |pages=13–15 |url=https://books.google.com/books?id=Sk0JBAAAQBAJ&q=malaria+reptile&pg=PA13 |access-date=15 March 2018}}</ref>

Humans are primarily infected by [[List of Plasmodium species infecting primates#Species infecting humans|five species]] of ''Plasmodium'', with the overwhelming majority of severe disease and death caused by ''[[Plasmodium falciparum]]''.<ref name=Scully>{{cite journal |doi=10.1016/j.mib.2017.10.006|pmid=29096194|pmc=5733638 |title=Molecular interactions governing host-specificity of blood stage malaria parasites|journal=Current Opinion in Microbiology |volume=40|pages=21–31 |year=2017 |last1=Scully |first1=Erik J. |last2=Kanjee|first2=Usheer|last3=Duraisingh|first3=Manoj T.}}</ref> Some species that infect humans can also infect other primates, and zoonoses of certain species (e.g. ''[[Plasmodium knowlesi|P. knowlesi]]'') from other primates to humans are common.<ref name=Scully/> Non-human primates also contain a [[List of Plasmodium species infecting primates|variety of ''Plasmodium'' species]] that do not generally infect humans. Some of these can cause severe disease in primates, while others can remain in the host for prolonged periods without causing disease.<ref name=Nunn>{{cite book |author1=Nunn, C. |author2=Altizer, S. |date=2006 |title=Infectious Diseases in Primates: Behavior, Ecology and Evolution |url=https://books.google.com/books?id=1s0TDAAAQBAJ&q=plasmodium&pg=PA254 |edition=1st |publisher=Oxford University Press |pages=253–254 |isbn=978-0198565840 |access-date=16 March 2018}}</ref> Many other mammals also carry [[Vinckeia|''Plasmodium'' species]], such as a variety of [[rodents]], [[ungulates]], and [[bat]]s. Again, some species of ''Plasmodium'' can cause severe disease in some of these hosts, while many appear not to.<ref>{{cite journal|title=The rediscovery of malaria parasites of ungulates |journal=Parasitology |volume=143 |issue=12 |date=2016 |pages=1501–1508 |vauthors=Templeton TJ, Martinsen E, Kaewthamasorn M, Kaneko O |doi=10.1017/S0031182016001141|pmid=27444556 |s2cid=22397021 }}</ref>

[[List of Plasmodium species infecting birds|Over 150 species of ''Plasmodium'']] infect a broad variety of birds. In general each species of ''Plasmodium'' infects one to a few species of birds.<ref name=Valkiunas2>{{cite book|title=Avian Malaria Parasites and Other Haemosporidia |author=Valkiunas, Gediminas |publisher=CRC Press |isbn=9780415300971 |date=2004 |chapter=Specificity and general Principles of Species Identification |pages=67–81}}</ref> ''Plasmodium'' parasites that infect birds tend to persist in a given host for years or for the life time of the host, although in some cases ''Plasmodium'' infections can result in severe illness and rapid death.<ref name=Valkiunas>{{cite book|title=Avian Malaria Parasites and Other Haemosporidia |author=Valkiunas, Gediminas |publisher=CRC Press |isbn=9780415300971 |date=2004 |chapter=General Section - Life Cycle and Morphology of Plasmodiidae Species |pages=27–35}}</ref><ref name=Valkiunas3>{{cite book|title=Avian Malaria Parasites and Other Haemosporidia |author=Valkiunas, Gediminas  |publisher=CRC Press |isbn=9780415300971 |date=2004 |chapter=Pathogenicity |pages=83–111}}</ref> Unlike with ''Plasmodium'' species infecting mammals, those infecting birds are distributed across the globe.<ref name=Valkiunas2/>

[[List of Plasmodium species infecting reptiles|Species from several subgenera]] of ''Plasmodium'' infect diverse [[reptiles]]. ''Plasmodium'' parasites have been described in most lizard [[Family (biology)|families]] and, like avian parasites, are spread worldwide.<ref name=Zug>{{cite book|title=Herpetology: An Introductory Biology of Amphibians and Reptiles |editor1=Zug, G. R. |editor2=Vitt, L. J. |isbn=978-0127826202 |publisher=Academic Press |date=2012 |url=https://books.google.com/books?id=nqgpcru2sfwC&q=malaria+reptile&pg=PA152 |access-date=16 March 2018 |page=152}}</ref> Again, parasites can result either in severe disease or be apparently asymptomatic depending on the parasite and the host.<ref name=Zug/>

A number of [[Antimalarial medication|drugs]] have been developed over the years to control ''Plasmodium'' infection in vertebrate hosts, particularly in humans. [[Quinine]] was used as a frontline antimalarial from the 17th century until widespread [[antimicrobial resistance|resistance]] emerged in the early 20th century.<ref name="Blasco2018">{{cite journal |last1=Blasco |first1=Benjamin |last2=Leroy |first2=Didier |last3=Fidock |first3=David A. |author-link3=David A. Fidock |year=2017 |title=Antimalarial drug resistance: Linking Plasmodium falciparum parasite biology to the clinic |journal=Nature Medicine |volume=23 |issue=8 |pages=917–928 |doi=10.1038/nm.4381 |pmc=5747363 |pmid=28777791}}</ref> Resistance to quinine spurred the development of a broad array of antimalarial medications through the 20th century including [[chloroquine]], [[proguanil]], [[atovaquone]], [[sulfadoxine/pyrimethamine]], [[mefloquine]], and [[artemisinin]].<ref name=Blasco2018/> In all cases, parasites resistant to a given drug have emerged within a few decades of the drugs deployment.<ref name=Blasco2018/> To combat this, antimalarial drugs are frequently used in combination, with [[artemisinin combination therapy|artemisinin combination therapies]] currently the gold standard for treatment.<ref name=Cowman2016>{{cite journal |doi=10.1016/j.cell.2016.07.055 |pmid=27768886|title=Malaria: Biology and Disease |journal=Cell |volume=167|issue=3 |pages=610–624|year=2016|last1=Cowman |first1=Alan F|last2=Healer|first2=Julie |last3=Marapana |first3=Danushka|last4=Marsh |first4=Kevin|doi-access=free}}</ref> In general, antimalarial drugs target the life stages of ''Plasmodium'' parasites that reside within vertebrate red blood cells, as these are the stages that tend to cause disease.<ref name=Haldar2018>{{cite journal|doi=10.1038/nrmicro.2017.161 |pmid=29355852|pmc=6371404|title=Drug resistance in Plasmodium |journal=Nature Reviews Microbiology|volume=16|issue=3 |pages=156–170 |year=2018|last1=Haldar |first1=Kasturi |last2=Bhattacharjee|first2=Souvik|last3=Safeukui|first3=Innocent}}</ref> However, drugs targeting other stages of the parasite life cycle are under development in order to prevent infection in travelers and to prevent transmission of sexual stages to insect hosts.<ref>{{cite journal|doi=10.1002/med.21486 |pmid=29372568 |title=Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication |journal=Medicinal Research Reviews |volume=38 |issue=5 |pages=1511–1535 |year=2018 |last1=Poonam |last2=Gupta |first2=Yash |last3=Gupta |first3=Nikesh |last4=Singh |first4=Snigdha |last5=Wu |first5=Lidong |last6=Chhikara |first6=Bhupender Singh |last7=Rawat |first7=Manmeet |last8=Rathi |first8=Brijesh |s2cid=25711437 }}</ref>

<gallery widths="200px" heights="160px">
File:Saving_Lives_with_SMS_for_Life.jpg|A clinic for treating human malaria in Tanzania
File:Anolis carolinensis.jpg|Over 3000 species of lizard, including the [[Carolina anole]] (''Anolis carolinensis''), carry some 90 kinds of malaria.
</gallery>

=== Insects ===
[[File:Anopheles stephensi.jpeg|thumb|The mosquito ''[[Anopheles stephensi]]'' is among the blood-feeding insects that can be infected by a species of ''Plasmodium''.]]

In addition to a vertebrate host, all ''Plasmodium'' species also infect a [[hematophagy|bloodsucking]] insect host, generally a mosquito (although some reptile-infecting parasites are transmitted by [[sandfly|sandflies]]). Mosquitoes of the genera ''[[Culex]]'', ''[[Anopheles]]'', ''[[Culiseta]]'', ''[[Mansonia (fly)|Mansonia]]'' and ''[[Aedes]]'' act as insect hosts for various ''Plasmodium'' species. The best studied of these are the ''Anopheles'' mosquitoes which host the ''Plasmodium'' parasites of human malaria, as well as ''Culex'' mosquitoes which host the ''Plasmodium'' species that cause malaria in birds. Only female mosquitoes are infected with ''Plasmodium'', since only they feed on the blood of vertebrate hosts.<ref>{{Cite journal |last1=Crompton |first1=Peter D. |last2=Moebius |first2=Jacqueline |last3=Portugal |first3=Silvia |last4=Waisberg |first4=Michael |last5=Hart |first5=Geoffrey |last6=Garver |first6=Lindsey S. |last7=Miller |first7=Louis H. |last8=Barillas-Mury |first8=Carolina |last9=Pierce |first9=Susan K. |date=2014 |title=Malaria Immunity in Man and Mosquito: Insights into Unsolved Mysteries of a Deadly Infectious Disease |journal=Annual Review of Immunology |volume=32 |issue=1 |pages=157–187 |doi=10.1146/annurev-immunol-032713-120220 |pmid=24655294 |pmc=4075043}}</ref> Different species affect their insect hosts differently. Sometimes, insects infected with ''Plasmodium'' have reduced lifespan and reduced ability to produce offspring.<ref name=Busula>{{cite journal |doi=10.1016/j.pt.2017.08.010 |pmid=28942108 |title=Mechanisms of Plasmodium -Enhanced Attraction of Mosquito Vectors |journal=Trends in Parasitology |volume=33 |issue=12 |pages=961–973 |year=2017 |last1=Busula |first1=Annette O. |last2=Verhulst |first2=Niels O. |last3=Bousema |first3=Teun |last4=Takken |first4=Willem |last5=De Boer |first5=Jetske G.}}</ref> Further, some species of ''Plasmodium'' appear to cause insects to prefer to bite infected vertebrate hosts over non-infected hosts.<ref name=Busula/><ref>{{cite journal |doi=10.1016/j.cois.2017.02.002 |pmid=28602239 |title=Effects of malaria infection on mosquito olfaction and behavior: Extrapolating data to the field |journal=Current Opinion in Insect Science |volume=20 |pages=7–12 |year=2017 |last1=Stanczyk |first1=Nina M. |last2=Mescher |first2=Mark C. |last3=De Moraes |first3=Consuelo M.|doi-access=free }}</ref><ref>{{cite journal |doi=10.1101/cshperspect.a025593 |pmid=28389513 |title=Anopheline Reproductive Biology: Impacts on Vectorial Capacity and Potential Avenues for Malaria Control |journal=Cold Spring Harbor Perspectives in Medicine |volume=7 |issue=12 |pages=a025593 |year=2017 |last1=Mitchell |first1=Sara N. |last2=Catteruccia |first2=Flaminia|pmc=5710097 |author-link2=Flaminia Catteruccia}}</ref>

== History ==
[[Charles Louis Alphonse Laveran]] first described parasites in the blood of malaria patients in 1880.<ref name=CDCHistory>{{cite web|url=https://www.cdc.gov/malaria/about/history/index.html |access-date=31 May 2016 |title=The History of Malaria, an Ancient Disease |publisher=U.S. Centers for Disease Control and Prevention}}</ref> He named the parasite ''Oscillaria malariae''.<ref name=CDCHistory/> In 1885, zoologists [[Ettore Marchiafava]] and [[Angelo Celli]] reexamined the parasite and termed it a member of a new genus, ''Plasmodium'', named for the resemblance to the [[Plasmodium (life cycle)|multinucleate cells]] of [[slime molds]] of the same name.<ref name=McFadden2012>{{cite journal | last1 = McFadden | first1 = G. I. | year = 2012 | title = Plasmodia – don't | journal = Trends Parasitol | volume = 28 | issue = 8 | pages = 306 | doi=10.1016/j.pt.2012.05.006 | pmid = 22738856}}</ref>{{refn|group=notes|The plural of ''Plasmodium'' is not ''Plasmodia''. Instead multiple species of the genus are referred to as "''Plasmodium'' species".<ref name=McFadden2012/>}} The fact that several species may be involved in causing different forms of malaria was first recognized by [[Camillo Golgi]] in 1886.<ref name=CDCHistory/> Soon thereafter, [[Giovanni Batista Grassi]] and [[Raimondo Filetti]] named the parasites causing two different types of human malaria ''[[Plasmodium vivax]]'' and ''[[Plasmodium malariae]]''.<ref name=CDCHistory/> In 1897, [[William H. Welch|William Welch]] identified and named ''[[Plasmodium falciparum]]''. This was followed by the recognition of the other two species of ''Plasmodium'' which infect humans: ''[[Plasmodium ovale]]'' (1922) and ''[[Plasmodium knowlesi]]'' (identified in [[long-tailed macaque]]s in 1931; in humans in 1965).<ref name=CDCHistory/> The contribution of insect hosts to the ''Plasmodium'' life cycle was described in 1897 by [[Ronald Ross]] and in 1899 by Giovanni Batista Grassi, [[Amico Bignami]] and [[Giuseppe Bastianelli]].<ref name=CDCHistory/>

In 1966, [[Cyril Garnham]] proposed separating ''Plasmodium'' into nine subgenera based on host specificity and parasite morphology.<ref name=Martinsen2013/> This included four subgenera that had previously been proposed for bird-infecting ''Plasmodium'' species by A. Corradetti in 1963.<ref name="Corradetti1963">{{cite journal |author1=Corradetti A. |author2=Garnham P.C.C. |author3=Laird M. |title=New classification of the avian malaria parasites |journal=Parassitologia |volume=5 |pages=1–4 |year=1963 }}</ref><ref name=Valkiunas4/> This scheme was expanded upon by Sam R. Telford in 1988 when he reclassified ''Plasmodium'' parasites that infect reptiles, adding five subgenera.<ref name="Telford1988">{{cite journal |author=Telford S |title=A contribution to the systematics of the reptilian malaria parasites, family Plasmodiidae (Apicomplexa: Haemosporina) |journal=Bulletin of the Florida State Museum Biological Sciences |volume=34 |issue=2 |pages=65–96 |year=1988 |url=http://ufdcweb1.uflib.ufl.edu/UF00095820/00001/3 |access-date=2014-03-25 |archive-date=2018-09-26 |archive-url=https://web.archive.org/web/20180926161500/http://ufdcweb1.uflib.ufl.edu/UF00095820/00001/3 |url-status=dead }}</ref><ref name=Martinsen2013/> In 1997, G. Valkiunas reclassified the bird-infecting ''Plasmodium'' species adding a fifth subgenus: ''Bennettinia''.<ref name=Valkiunas4/><ref name="Valkiunas1997">{{cite journal |author=Valkiunas, G. |title=Bird Haemosporidia |journal=Acta Zoologica Lituanica |volume=3–5 |pages=1–607 |year=1997 |issn=1392-1657 }}</ref>

==See also==
* [[Haematozoa]]
* [[List of Plasmodium species]]
* [[Plasmodium molecular tools]]

== Notes==
{{Reflist|group=notes}}

== References ==
{{Reflist}}

== Further reading ==
===Identification===

* {{cite book |last=Garnham |first=P. C. |title=Malaria Parasites And Other Haemosporidia |publisher=Blackwell |location=Oxford |year=1966 |isbn=978-0397601325}}
* {{cite book |last=Valkiunas |first=Gediminas |title=Avian Malaria Parasites and Other Haemosporidia |publisher=CRC Press |location=Boca Raton |year=2005 |isbn=9780415300971}}

===Biology===
* {{cite journal |author1=Baldacci, P. |author2=Ménard, R. |title=The elusive malaria sporozoite in the mammalian host |journal=Mol. Microbiol. |volume=54 |issue=2 |pages=298–306 |date=October 2004 |pmid=15469504 |doi=10.1111/j.1365-2958.2004.04275.x |s2cid=30488807 |doi-access=free }}
* {{cite journal |author=Bledsoe, G. H. |title=Malaria primer for clinicians in the United States |journal=South. Med. J. |volume=98 |issue=12 |pages=1197–204; quiz 1205, 1230 |date=December 2005 |pmid=16440920 |url=http://www.sma.org/pdfs/objecttypes/smj/91C48D32-BCD4-FF25-565C69314AF7EB48/1196.pdf |doi=10.1097/01.smj.0000189904.50838.eb |s2cid=30660702 |url-status=dead |archive-url=https://web.archive.org/web/20090326131858/http://www.sma.org/pdfs/objecttypes/smj/91C48D32-BCD4-FF25-565C69314AF7EB48/1196.pdf |archive-date=2009-03-26 }}
* {{cite journal |author=Shortt, H. E. |title=Life-cycle of the mammalian malaria parasite |journal=Br. Med. Bull. |volume=8 |issue=1 |pages=7–9 |year=1951 |pmid=14944807 |doi=10.1093/oxfordjournals.bmb.a074057 }}

===History===
* {{cite journal |author=Slater, L. B. |title=Malarial birds: modeling infectious human disease in animals |journal=Bull Hist Med |volume=79 |issue=2 |pages=261–94 |year=2005 |pmid=15965289 |doi=10.1353/bhm.2005.0092 |s2cid=23594155 }}

==External links==
{{Wikispecies|Plasmodium}}
{{Commons category}}
* [https://web.archive.org/web/20150330171641/http://www.map.ox.ac.uk/ Malaria Atlas Project]
* [https://www.wehi.edu.au/wehi-tv?topic%5B%5D=77 Plasmodium lifecycle animation]

{{Malaria}}
{{Taxonbar|from=Q130948}}
{{Authority control}}

[[Category:Plasmodium| ]]
[[Category:Apicomplexa genera]]
[[Category:Malaria]]