Editing Plasmodium falciparum

{{Short description|Protozoan species of malaria parasite}}
{{Speciesbox
| taxon = Plasmodium falciparum
| image = Plasmodium falciparum 01.png
| image_caption = Macrogametocyte (left) and microgametocyte (right) of ''P. falciparum''
| authority = ([[William H. Welch|Welch]], 1897)
| synonyms =
* ''Oscillaria malariae'' <small>Laveran, 1881</small>
* ''Plasmodium malariae'' <small>Marchiafava and Celli, 1885</small>
* ''Laverania malariae'' <small>Feletti and Grassi, 1890</small>
* ''Ematozoo falciforme'' <small>Antolisei and Angelini, 1890</small>
* ''Haemamoeba immaculata'' <small>Grassi, 1891</small>
* ''Haemamoeba laverani'' <small>Labbe, 1894</small>
* ''Haematozoon falciforme'' <small>Thayer and Hewetson, 1895</small>
* ''Haematozoon falciparum'' <small>Welch, 1897</small>
* ''Haemosporidium sedecimanae'' <small>Lewkowicz, 1897</small>
* ''Haemosporidium undecimanae'' <small>Lewkowicz, 1897</small>
* ''Haemosporidium vigesimotertianae'' <small>Lewkowicz, 1897</small>
| synonyms_ref = <ref>{{cite book|last1=Coatney |first1=GR |last2=Collins |first2=WE |last3=Warren |first3=M |last4=Contacos |first4=PG|year=1971|title=The primate malarias|publisher=Division of Parasitic Disease, CDC|chapter=22 ''Plasmodium falciparum'' (Welch, 1897)|pages=263|chapter-url=http://stacks.cdc.gov/view/cdc/6538}}</ref>
}}

'''''Plasmodium falciparum''''' is a [[Unicellular organism|unicellular]] [[protozoa]]n [[parasite]] of [[human]]s, and the deadliest species of ''[[Plasmodium]]'' that causes [[malaria]] in humans.<ref>{{Cite journal | last1 = Rich | first1 = S. M. | last2 = Leendertz | first2 = F. H. | last3 = Xu | first3 = G. | last4 = Lebreton | first4 = M. | last5 = Djoko | first5 = C. F. | last6 = Aminake | first6 = M. N. | last7 = Takang | first7 = E. E. | last8 = Diffo | first8 = J. L. D. | last9 = Pike | first9 = B. L. | last10 = Rosenthal | doi = 10.1073/pnas.0907740106 | first10 = B. M. | last11 = Formenty | first11 = P. | last12 = Boesch | first12 = C. | last13 = Ayala | first13 = F. J. | last14 = Wolfe | first14 = N. D. | title = The origin of malignant malaria | journal = Proceedings of the National Academy of Sciences | volume = 106 | issue = 35 | pages = 14902–14907 | year = 2009 | pmid = 19666593 | pmc =2720412 | bibcode = 2009PNAS..10614902R | doi-access = free }}</ref> The parasite is transmitted through the bite of a female ''[[Anopheles]]'' [[mosquito]] and causes the disease's most dangerous form, falciparum malaria. ''P. falciparum'' is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer ([[Burkitt's lymphoma]]) and is classified as a [[List of IARC Group 2A carcinogens|Group 2A (probable) carcinogen]].

The species originated from the malarial parasite ''[[Laverania]]'' found in [[gorilla]]s, around 10,000 years ago.<ref name=loy>{{cite journal|last1=Loy|first1=Dorothy E.|last2=Liu|first2=Weimin|last3=Li|first3=Yingying|last4=Learn|first4=Gerald H.|last5=Plenderleith|first5=Lindsey J.|last6=Sundararaman|first6=Sesh A.|last7=Sharp|first7=Paul M.|last8=Hahn|first8=Beatrice H.|title=Out of Africa: origins and evolution of the human malaria parasites ''Plasmodium falciparum'' and ''Plasmodium vivax''|journal=International Journal for Parasitology|date=2017|volume=47|issue=2–3|pages=87–97|doi=10.1016/j.ijpara.2016.05.008|pmid=27381764|pmc=5205579}}</ref><ref name=":2">{{Cite journal |last1=Sharp |first1=Paul M. |last2=Plenderleith |first2=Lindsey J. |last3=Hahn |first3=Beatrice H. |date=2020 |title=Ape origins of human malaria |journal=Annual Review of Microbiology |volume=74 |pages=39–63 |doi=10.1146/annurev-micro-020518-115628 |pmc=7643433 |pmid=32905751}}</ref> [[Alphonse Laveran]] was the first to identify the parasite in 1880, and named it ''Oscillaria malariae''. [[Ronald Ross]] discovered its transmission by mosquito in 1897. [[Giovanni Battista Grassi]] elucidated the complete transmission from a female [[Anopheles|anopheline mosquito]] to humans in 1898. In 1897, [[William H. Welch]] created the name ''Plasmodium falciparum'', which [[International Commission on Zoological Nomenclature|ICZN]] formally adopted in 1954. ''P. falciparum'' assumes several different forms during its life cycle. The human-infective stage are [[sporozoites]] from the [[Salivary gland#Other animals|salivary gland of a mosquito]]. The sporozoites grow and multiply in the [[liver]] to become [[merozoites]]. These merozoites invade the [[Red blood cell|erythrocytes]] (red blood cells) to form [[trophozoites]], [[schizogony|schizonts]] and [[gametocytes]], during which the symptoms of malaria are produced. In the mosquito, the gametocytes undergo sexual reproduction to a [[zygote]], which turns into [[Apicomplexan life cycle#ookinete|ookinete]]. Ookinete forms [[oocyte]]s from which sporozoites are formed.

In 2022, some 249 million cases of malaria worldwide resulted in an estimated 608,000 deaths, with 80 percent being 5 years old or less.<ref>{{Cite web |title=World malaria report 2022 |url=https://www.who.int/publications-detail-redirect/9789240064898 |access-date=2024-01-30 |website=www.who.int |language=en}}</ref> Nearly all malarial deaths are caused by ''P. falciparum'', and 95% of such cases occur in [[Africa]]. In Sub-Saharan Africa, almost 100% of cases were due to ''P. falciparum'', whereas in most other regions where malaria is endemic, other, less virulent plasmodial species predominate.<ref name="who2020">{{cite book|last1=WHO|url=https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021|title=World Malaria Report 2021|date=2021|publisher=World Health Organization|isbn=978-92-4-004049-6|location=Switzerland}}</ref>

== History ==
[[File:Laveran Malaria drawings.jpg|thumb|Laveran's drawing of various stages of ''P. falciparum'' as seen on fresh blood (1880).]]
Falciparum malaria was familiar to the [[ancient Greece|ancient Greeks]], who gave the general name {{lang|grc|πυρετός}} (''pyretós'') "fever".<ref>{{cite journal|last1=Baron|first1=Christopher|last2=Hamlin|first2=Christopher|title=Malaria and the Decline of Ancient Greece: Revisiting the Jones Hypothesis in an Era of Interdisciplinarity|journal=Minerva|date=2015|volume=53|issue=4|pages=327–358|doi=10.1007/s11024-015-9280-7|s2cid=142602810}}</ref> [[Hippocrates]] (c. 460–370 BCE) gave several descriptions on [[Fever#Types|tertian fever and quartan fever]].<ref name=":0">{{cite journal|last1=Hempelmann|first1=Ernst|last2=Krafts|first2=Kristine|title=Bad air, amulets and mosquitoes: 2,000?years of changing perspectives on malaria|journal=Malaria Journal|date=2013|volume=12|issue=1|pages=232|doi=10.1186/1475-2875-12-232|pmid=23835014|pmc=3723432 |doi-access=free }}</ref> It was prevalent throughout the ancient Egyptian and Roman civilizations.<ref>{{cite journal|last1=Nerlich|first1=Andreas|title=Paleopathology and Paleomicrobiology of Malaria|journal=Microbiology Spectrum|date=2016|volume=4|issue=6|pages=155–160|doi=10.1128/microbiolspec.PoH-0006-2015|pmid=27837743|isbn=9781555819163}}</ref> It was the Romans who named the disease "malaria"—''mala'' for bad, and ''aria'' for air, as they believed that the disease was spread by contaminated air, or [[miasma theory|miasma]].<ref name=":0" /><ref name="lalchhandama" />

===Discovery===
A German physician, [[Johann Friedrich Meckel]], must have been the first to see ''P. falciparum'' but without knowing what it was. In 1847, he reported the presence of black pigment granules from the blood and spleen of a patient who died of malaria. The French Army physician [[Charles Louis Alphonse Laveran]], while working at Bône Hospital (now [[Annaba]] in Algeria), correctly identified the parasite as a causative pathogen of malaria in 1880. He presented his discovery before the [[French Academy of Medicine]] in Paris and published it in ''[[The Lancet]]'' in 1881. He gave it the scientific name ''Oscillaria malariae''.<ref name=lalchhandama>{{cite journal|last1=Lalchhandama|first1=K.|title=The making of modern malariology: from miasma to mosquito- malaria theory|journal=Science Vision|date=2014|volume=14|issue=1|pages=3–17|url=http://www.sciencevision.org/current_issue/dl/Lalchhandama.pdf|url-status=dead|archive-url=https://web.archive.org/web/20140427025145/http://www.sciencevision.org/current_issue/dl/Lalchhandama.pdf|archive-date=2014-04-27}}</ref> However, his discovery was received with skepticism, mainly because by that time, leading physicians such as [[Edwin Klebs|Theodor Albrecht Edwin Klebs]] and [[Corrado Tommasi-Crudeli]] claimed that they had discovered a bacterium (which they called ''Bacillus malariae'') as the pathogen of malaria. Laveran's discovery was only widely accepted after five years when [[Camillo Golgi]] confirmed the parasite using better microscopes and staining techniques. Laveran was awarded the [[Nobel Prize in Physiology or Medicine]] in 1907 for his work. In 1900, the Italian zoologist [[Giovanni Battista Grassi]] categorized ''[[Plasmodium]]'' species based on the timing of fever in the patient; malignant tertian malaria was caused by ''Laverania malariae'' (now ''P. falciparum''), benign tertian malaria by ''Haemamoeba vivax'' (now ''[[Plasmodium vivax|P. vivax]]''), and quartan malaria by ''Haemamoeba malariae'' (now ''[[Plasmodium malariae|P. malariae]]'').<ref>{{cite journal|last1=Cox|first1=Francis EG|title=History of the discovery of the malaria parasites and their vectors|journal=Parasites & Vectors|date=2010|volume=3|issue=1|pages=5|doi=10.1186/1756-3305-3-5|pmid=20205846|pmc=2825508 |doi-access=free }}{{open access}}</ref>

The British physician [[Patrick Manson]] formulated the [[mosquito-malaria theory]] in 1894; until that time, malarial parasites were believed to be spread in air as miasma, a Greek word for pollution.<ref name=lalchhandama/> His colleague [[Ronald Ross]] of the Indian Medical Service validated the theory while working in India. Ross discovered in 1897 that malarial parasites lived in certain mosquitoes. The next year, he demonstrated that a malarial parasite of birds could be transmitted by mosquitoes from one bird to another. Around the same time, Grassi demonstrated that ''P. falciparum'' was transmitted in humans only by female [[Anopheles|anopheline mosquito]] (in his case ''[[Anopheles claviger]]'').<ref>{{cite journal|last1=Baccetti|first1=B|title=History of the early dipteran systematics in Italy: from Lyncei to Battista Grassi|journal=Parassitologia|date=2008|volume=50|issue=3–4|pages=167–172|pmid=20055226}}</ref> Ross, Manson and Grassi were nominated for the Nobel Prize in Physiology or Medicine in 1902. Under controversial circumstances, only Ross was selected for the award.<ref>{{cite journal|last1=Capanna|first1=E|title=Grassi versus Ross: who solved the riddle of malaria?|journal=International Microbiology|date=2006|volume=9|issue=1|pages=69–74|pmid=16636993}}</ref>

There was a long debate on the taxonomy. It was only in 1954 the [[International Commission on Zoological Nomenclature]] officially approved the binominal ''Plasmodium falciparum''.<ref name=chwatt>{{cite journal|last1=Bruce-Chwatt|first1=L.J.|title=Falciparum nomenclature|journal=Parasitology Today|date=1987|volume=3|issue=8|pages=252|doi=10.1016/0169-4758(87)90153-0|pmid=15462972}}</ref> The valid genus ''Plasmodium'' was created by two Italian physicians [[Ettore Marchiafava]] and [[Angelo Celli]] in 1885. The Greek word ''plasma'' means "mould" or "form"; ''oeidēs'' means "to see" or "to know." The species name was introduced by an American physician [[William Henry Welch]] in 1897.<ref>{{cite journal|last1=Christophers|first1=R|last2=Sinton|first2=JA|title=Correct Name of Malignant Tertian Parasite|journal=British Medical Journal|date=1938|volume=2|issue=4065|pages=1130–1134|pmid=20781927|pmc=2211005|doi=10.1136/bmj.2.4065.1130}}</ref> It is derived from the Latin ''falx'', meaning "sickle" and ''parum'' meaning "like or equal to another".<ref name=chwatt/>

=== Origin and evolution ===
''P. falciparum'' is now generally accepted to have evolved from ''[[Laverania]]'' (a subgenus of ''Plasmodium'' found in apes) species present in gorillas in Western Africa.<ref>{{cite journal|last1=Liu|first1=W|last2=Li|first2=Y|last3=Learn|first3=GH|last4=Rudicell|first4=RS|last5=Robertson|first5=JD|last6=Keele|first6=BF|last7=Ndjango|first7=JB|last8=Sanz|first8=CM|last9=Morgan|first9=DB|last10=Locatelli|first10=S|last11=Gonder|first11=MK|last12=Kranzusch|first12=PJ|last13=Walsh|first13=PD|last14=Delaporte|first14=E|last15=Mpoudi-Ngole|first15=E|last16=Georgiev|first16=AV|last17=Muller|first17=MN|last18=Shaw|first18=GM|last19=Peeters|first19=M|last20=Sharp|first20=PM|last21=Rayner|first21=JC|last22=Hahn|first22=BH|title=Origin of the human malaria parasite'' Plasmodium falciparum'' in gorillas|journal=Nature|date= 2010|volume=467|issue=7314|pages=420–5|doi=10.1038/nature09442|pmid=20864995|pmc=2997044|display-authors=8|bibcode=2010Natur.467..420L}}</ref><ref>{{cite journal|last1=Holmes|first1=Edward C.|title=Malaria: The gorilla connection|journal=Nature|date=2010|volume=467|issue=7314|pages=404–405|doi=10.1038/467404a|pmid=20864986|bibcode=2010Natur.467..404H|s2cid=205058952|doi-access=free}}</ref> Genetic diversity indicates that the human protozoan emerged around 10,000 years ago.<ref name=loy/><ref name=":2" /> The closest relative of ''P. falciparum'' is ''P. praefalciparum'', a parasite of [[gorilla]]s, as supported by [[mitochondrial DNA|mitochondrial]], [[apicoplast]]ic and [[nuclear DNA]] sequences.<ref name="Liu et al. 2010">{{cite journal |last1=Liu |first1=Weimin |last2=Li |first2=Yingying |last3=Learn |first3=Gerald H. |last4=Rudicell |first4=Rebecca S. |last5=Robertson |first5=Joel D. |last6=Keele |first6=Brandon F. |last7=Ndjango |first7=Jean-Bosco N. |last8=Sanz |first8=Crickette M. |last9=Morgan |first9=David B. |last10=Locatelli |first10=Sabrina |last11=Gonder |first11=Mary K. |last12=Kranzusch |first12=Philip J. |last13=Walsh |first13=Peter D. |last14=Delaporte |first14=Eric |last15=Mpoudi-Ngole |first15=Eitel |last16=Georgiev |first16=Alexander V. |last17=Muller |first17=Martin N. |last18=Shaw |first18=George M. |last19=Peeters |first19=Martine |last20=Sharp |first20=Paul M. |last21=Rayner |first21=Julian C. |last22=Hahn |first22=Beatrice H. |title=Origin of the human malaria parasite ''Plasmodium falciparum'' in gorillas |journal=Nature |date=September 2010 |volume=467 |issue=7314 |pages=420–425 |doi=10.1038/nature09442 |bibcode = 2010Natur.467..420L| pmid=20864995
| pmc=2997044}}</ref><ref name="Duval et al. 2010">{{cite journal |last1=Duval |first1=Linda |last2=Fourment |first2=Mathieu |last3=Nerrienet |first3=Eric |last4=Rousset |first4=Dominique |last5=Sadeuh |first5=Serge A. |last6=Goodman |first6=Steven M. |last7=Andriaholinirina |first7=Nicole V. |last8=Randrianarivelojosia |first8=Milijaona |last9=Paul |first9=Richard E. |last10=Robert |first10=Vincent |last11=Ayala |first11=Francisco J. |last12=Ariey |first12=Frédéric |title=African apes as reservoirs of ''Plasmodium falciparum'' and the origin and diversification of the Laverania subgenus |journal=Proceedings of the National Academy of Sciences |date=8 June 2010 |volume=107 |issue=23 |pages=10561–10566 |doi=10.1073/pnas.1005435107 |pmid=20498054 |pmc=2890828 |bibcode=2010PNAS..10710561D |doi-access = free
}}</ref><ref name="Rayner et al. 2010">{{cite journal |last1=Rayner |first1=Julian C. |last2=Liu |first2=Weimin |last3=Peeters |first3=Martine |last4=Sharp |first4=Paul M. |last5=Hahn |first5=Beatrice H. |title=A plethora of Plasmodium species in wild apes: a source of human infection? |journal=Trends in Parasitology |date=May 2011 |volume=27 |issue=5 |pages=222–229 |doi=10.1016/J.Pt.2011.01.006 |pmid=21354860 |pmc=3087880}}</ref> These two species are closely related to the [[Common chimpanzee|chimpanzee]] parasite ''P. reichenowi'', which was previously thought to be the closest relative of ''P. falciparum''. ''P. falciparum'' was also once thought to originate from a parasite of birds.<ref name="Rathore et al. 2001">{{cite journal |last1=Rathore |first1=Dharmendar |last2=Wahl |first2=Allison M |last3=Sullivan |first3=Margery |last4=McCutchan |first4=Thomas F |title=A phylogenetic comparison of gene trees constructed from plastid, mitochondrial and genomic DNA of Plasmodium species |journal=Molecular and Biochemical Parasitology |date=April 2001 |volume=114 |issue=1 |pages=89–94 |doi=10.1016/S0166-6851(01)00241-9}}</ref>

Levels of genetic [[Polymorphism (biology)|polymorphism]] are extremely low within the ''P. falciparum'' genome compared to that of closely related, ape infecting species of ''Plasmodium'' (including ''P. praefalciparum'').<ref name="Hartl 2004">{{Cite journal| volume = 2| issue = 1| pages = 15–22| last = Hartl| first = DH| title = The origin of malaria: mixed messages from genetic diversity| journal = Nature Reviews Microbiology| date = January 2004
| pmid=15035005| doi = 10.1038/nrmicro795| s2cid = 11020105}}</ref><ref name="Liu et al. 2010" /> This suggests that the origin of ''P. falciparum'' in humans is recent, as a single ''P. praefalciparum'' strain became capable of infecting humans.<ref name="Liu et al. 2010" /> The genetic information of ''P. falciparum'' has signaled a recent expansion that coincides with the agricultural revolution. The development of extensive agriculture likely increased mosquito population densities by giving rise to more breeding sites, which may have triggered the evolution and expansion of ''P. falciparum''.<ref>{{cite journal | last1 = Hume | first1 = J.C. | last2 = Lyons | first2 = E.J. | last3 = Day | first3 = K.P. | year = 2003 | title = Human migration, mosquitoes and the evolution of ''Plasmodium falciparum'' | journal = Trends Parasitol | volume = 19 | issue = 3| pages = 144–9 | doi=10.1016/s1471-4922(03)00008-4| pmid = 12643998 }}</ref>

== Structure ==
[[File:Plasmodium falciparum 02.jpg|thumb|Blood smear from a ''P. falciparum'' [[Malaria culture|culture]] (K1 strain - asexual forms) - several red blood cells have ring stages inside them. Close to the center is a schizont and on the left a trophozoite.]]
[[File:Malaria falciparum ring forms.jpg|right|thumb|Ring forms in red blood cells (Giemsa stain)]]
''P. falciparum'' does not have a fixed structure but undergoes continuous change during its life cycle. A sporozoite is spindle-shaped and 10–15 μm long. In the liver, it grows into an ovoid schizont of 30–70 μm in diameter. Each schizont produces merozoites, each of which is roughly 1.5 μm in length and 1 μm in diameter. In the erythrocyte the merozoite forms a ring-like structure, becoming a trophozoite. A trophozoite feeds on the haemoglobin and forms a granular pigment called [[haemozoin]]. Unlike those of other ''Plasmodium'' species, the gametocytes of ''P. falciparum'' are elongated and crescent-shaped, by which they are sometimes identified. A mature gametocyte is 8–12 μm long and 3–6 μm wide. The ookinete is also elongated measuring about 18–24 μm. An oocyst is rounded and can grow up to 80 μm in diameter.<ref>{{cite book|last1=Lucius|first1=R.|last2=Roberts|first2=C.W.|editor1-last=Lucius|editor1-first=R.|editor2-last=Loos-Frank|editor2-first=B.|editor3-last=Lane|editor3-first=R.P.|editor4-last=Poulin|editor4-first=R.|editor5-last=Roberts|editor5-first=C.W.|editor6-last=Grencis|editor6-first=R.K.|title=The Biology of Parasites|date=2017|publisher=John Wiley & Sons|isbn=978-3-527-32848-2|pages=190–198|chapter-url=https://books.google.com/books?id=w8bXDQAAQBAJ|chapter=Biology of Parasitic Protozoa}}</ref> Microscopic examination of a blood film reveals only early (ring-form) trophozoites and gametocytes that are in the peripheral blood. Mature trophozoites or schizonts in peripheral blood smears, as these are usually sequestered in the tissues. On occasion, faint, comma-shaped, red dots are seen on the erythrocyte surface. These dots are [[Maurer's cleft]] and are secretory organelles that produce proteins and enzymes essential for nutrient uptake and immune evasion processes.<ref>{{cite journal|last1=Lanzer|first1=Michael|last2=Wickert|first2=Hannes|last3=Krohne|first3=Georg|last4=Vincensini|first4=Laetitia|last5=Braun Breton|first5=Catherine|title=Maurer's clefts: A novel multi-functional organelle in the cytoplasm of ''Plasmodium falciparum''-infected erythrocytes|journal=International Journal for Parasitology|date=2006|volume=36|issue=1|pages=23–36|doi=10.1016/j.ijpara.2005.10.001|pmid=16337634}}</ref>

The apical complex, which is a combination of organelles, is an important structure. It contains secretory organelles called rhoptries and micronemes, which are vital for mobility, adhesion, host cell invasion, and parasitophorous vacuole formation.<ref name=garcia06/> As an [[apicomplexan]], it harbours a plastid, an [[apicoplast]], similar to plant [[chloroplast]]s, which they probably acquired by engulfing (or being invaded by) a [[eukaryotic]] [[Algae|alga]] and retaining the algal plastid as a distinctive [[organelle]] [[Symbiogenesis|encased within four membranes]]. The apicoplast is involved in the synthesis of [[lipid]]s and several other compounds and provides an attractive drug target. During the asexual blood stage of infection, an essential function of the apicoplast is to produce the isoprenoid precursors [[isopentenyl pyrophosphate]] (IPP) and [[dimethylallyl pyrophosphate]] (DMAPP) via the [[MEP pathway|MEP (non-mevalonate) pathway]].<ref>{{Cite journal|last1=Yeh|first1=Ellen|last2=DeRisi|first2=Joseph L.|date=2011-08-30|title=Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage ''Plasmodium falciparum''|journal=PLOS Biol|volume=9|issue=8|pages=e1001138|doi=10.1371/journal.pbio.1001138|issn=1545-7885|pmc=3166167|pmid=21912516 |doi-access=free }}</ref>

=== Genome ===

In 1995 the Malaria Genome Project was set up to sequence the genome of ''P. falciparum''. The genome of its [[mitochondrion]] was reported in 1995, that of the nonphotosynthetic [[plastid]] known as the apicoplast in 1996,<ref>{{cite journal |last1=Wilson |first1=(Iain) R.J.M. |last2=Denny |first2=Paul W. |last3=Preiser |first3=Peter R. |last4=Rangachari |first4=Kaveri |last5=Roberts |first5=Kate |last6=Roy |first6=Anjana |last7=Whyte |first7=Andrea |last8=Strath |first8=Malcolm |last9=Moore |first9=Daphne J. |last10=Moore |first10=Peter W. |last11=Williamson |first11=Donald H. |title=Complete Gene Map of the Plastid-like DNA of the Malaria Parasite ''Plasmodium falciparum'' |journal=Journal of Molecular Biology |date=August 1996 |volume=261 |issue=2 |pages=155–172 |doi=10.1006/jmbi.1996.0449}}</ref> and the sequence of the first nuclear [[chromosome]] (chromosome 2) in 1998. The sequence of chromosome 3 was reported in 1999 and the entire genome was reported on 3 October 2002.<ref name="gardner">{{cite journal |last1=Gardner |first1=Malcolm J. |last2=Hall |first2=Neil |last3=Fung |first3=Eula |last4=White |first4=Owen |last5=Berriman |first5=Matthew |last6=Hyman |first6=Richard W. |last7=Carlton |first7=Jane M. |last8=Pain |first8=Arnab |last9=Nelson |first9=Karen E. |last10=Bowman |first10=Sharen |last11=Paulsen |first11=Ian T. |last12=James |first12=Keith |last13=Eisen |first13=Jonathan A. |last14=Rutherford |first14=Kim |last15=Salzberg |first15=Steven L. |last16=Craig |first16=Alister |last17=Kyes |first17=Sue |last18=Chan |first18=Man-Suen |last19=Nene |first19=Vishvanath |last20=Shallom |first20=Shamira J. |last21=Suh |first21=Bernard |last22=Peterson |first22=Jeremy |last23=Angiuoli |first23=Sam |last24=Pertea |first24=Mihaela |last25=Allen |first25=Jonathan |last26=Selengut |first26=Jeremy |last27=Haft |first27=Daniel |last28=Mather |first28=Michael W. |last29=Vaidya |first29=Akhil B. |last30=Martin |first30=David M. A. |last31=Fairlamb |first31=Alan H. |last32=Fraunholz |first32=Martin J. |last33=Roos |first33=David S. |last34=Ralph |first34=Stuart A. |last35=McFadden |first35=Geoffrey I. |last36=Cummings |first36=Leda M. |last37=Subramanian |first37=G. Mani |last38=Mungall |first38=Chris |last39=Venter |first39=J. Craig |last40=Carucci |first40=Daniel J. |last41=Hoffman |first41=Stephen L. |last42=Newbold |first42=Chris |last43=Davis |first43=Ronald W. |last44=Fraser |first44=Claire M. |last45=Barrell |first45=Bart |title=Genome sequence of the human malaria parasite ''Plasmodium falciparum'' |journal=Nature |date=October 2002 |volume=419 |issue=6906 |pages=498–511 |doi=10.1038/nature01097|pmid=12368864 |bibcode=2002Natur.419..498G |pmc=3836256 }}</ref> The roughly 24-megabase genome is extremely AT-rich (about 80%) and is organised into 14 chromosomes. Just over 5,300 genes were described. Many genes involved in [[antigenic variation]] are located in the [[subtelomeric]] regions of the chromosomes. These are divided into the ''var'', ''rif'', and ''stevor'' families. Within the genome, there exist 59 ''var'', 149 ''rif'', and 28 ''stevor'' genes, along with multiple [[pseudogenes]] and truncations. It is estimated that 551, or roughly 10%, of the predicted nuclear-encoded [[proteins]] are targeted to the [[apicoplast]], while 4.7% of the [[proteome]] is targeted to the mitochondria.<ref name="gardner"/>

== Life cycle ==
[[File:Anopheles gambiae mosquito feeding 1354.p lores.jpg|alt=''Anopheles'' mosquito, the carrier of ''Plasmodium falciparum''|thumb|''Anopheles'' mosquito, the carrier of ''Plasmodium falciparum'']]
Humans are the intermediate hosts in which asexual reproduction occurs, and female anopheline mosquitos are the definitive hosts harbouring the sexual reproduction stage.<ref>{{Cite journal|last1=Lee|first1=Wenn-Chyau|last2=Russell|first2=Bruce|last3=Rénia|first3=Laurent|date=2019|title=Sticking for a Cause: The Falciparum Malaria Parasites Cytoadherence Paradigm|journal=Frontiers in Immunology|volume=10|pages=1444|doi=10.3389/fimmu.2019.01444|pmc=6610498|pmid=31316507|doi-access=free}}</ref>

===In humans===
[[File:Plasmodium lifecycle PHIL 3405 lores.jpg|thumb|right|Life cycle of ''Plasmodium'']]

Infection in humans begins with the bite of an infected female ''Anopheles'' mosquito. Out of about 460 species of ''[[Anopheles]]'' [[mosquito]], more than 70 species transmit falciparum malaria.<ref>{{cite journal|last1=Molina-Cruz|first1=Alvaro|last2=Zilversmit|first2=Martine M.|last3=Neafsey|first3=Daniel E.|last4=Hartl|first4=Daniel L.|last5=Barillas-Mury|first5=Carolina|title=Mosquito Vectors and the Globalization of ''Plasmodium falciparum'' Malaria|journal=Annual Review of Genetics|date=2016|volume=50|issue=1|pages=447–465|doi=10.1146/annurev-genet-120215-035211|pmid=27732796|url=https://zenodo.org/record/1235011}}</ref> ''[[Anopheles gambiae]]'' is one of the best known and most prevalent vectors, particularly in Africa.<ref>{{cite journal|last1=Sinka|first1=Marianne E|last2=Bangs|first2=Michael J|last3=Manguin|first3=Sylvie|last4=Coetzee|first4=Maureen|last5=Mbogo|first5=Charles M|last6=Hemingway|first6=Janet|last7=Patil|first7=Anand P|last8=Temperley|first8=Will H|last9=Gething|first9=Peter W|last10=Kabaria|first10=Caroline W|last11=Okara|first11=Robi M|last12=Van Boeckel|first12=Thomas|last13=Godfray|first13=H Charles J|last14=Harbach|first14=Ralph E|last15=Hay|first15=Simon I|title=The dominant ''Anopheles'' vectors of human malaria in Africa, Europe and the Middle East: occurrence data, distribution maps and bionomic pr?cis|journal=Parasites & Vectors|date=2010|volume=3|issue=1|pages=117|doi=10.1186/1756-3305-3-117|pmid=21129198|pmc=3016360 |doi-access=free }}</ref>

The infective stage called the [[Apicomplexan life cycle|sporozoite]] is released from the salivary glands through the proboscis of the mosquito to enter through the skin during feeding.<ref>{{cite journal |last1=Ménard |first1=R |last2=Tavares |first2=J |last3=Cockburn |first3=I |last4=Markus |first4=M |last5=Zavala |first5=F |last6=Amino |first6=R |title=Looking under the skin: the first steps in malarial infection and immunity |journal=Nature Reviews Microbiology |date=2013 |volume=11 |issue=10 |pages=701–712 |doi=10.1038/nrmicro3111 |pmid=24037451|s2cid=21437365 |doi-access=free }}</ref> The mosquito saliva contains antihaemostatic and anti-inflammatory enzymes that disrupt [[blood clotting]] and inhibit the pain reaction. Typically, each infected bite contains 20–200 sporozoites.<ref name=garcia06>{{cite journal|last1=Garcia|first1=J. E.|last2=Puentes|first2=A.|last3=Patarroyo|first3=M. E.|title=Developmental Biology of Sporozoite-Host Interactions in ''Plasmodium falciparum'' Malaria: Implications for Vaccine Design|journal=Clinical Microbiology Reviews|date=2006|volume=19|issue=4|pages=686–707|doi=10.1128/CMR.00063-05|pmid=17041140|pmc=1592691}}</ref> A proportion of sporozoites invade liver cells ([[hepatocyte]]s).<ref name="gerald">{{cite journal|last1=Gerald|first1=N.|last2=Mahajan|first2=B.|last3=Kumar|first3=S.|title=Mitosis in the Human Malaria Parasite ''Plasmodium falciparum''|journal=Eukaryotic Cell|date=2011|volume=10|issue=4|pages=474–482|doi=10.1128/EC.00314-10|pmid=21317311|pmc=3127633}}</ref> The sporozoites move in the bloodstream by [[gliding motility|gliding]], which is driven by a motor made up of the proteins [[actin]] and [[myosin]] beneath their [[plasma membrane]].<ref>{{cite journal|last1=Kappe|first1=SH|last2=Buscaglia|first2=CA|last3=Bergman|first3=LW|last4=Coppens|first4=I|last5=Nussenzweig|first5=V|title=Apicomplexan gliding motility and host cell invasion: overhauling the motor model|journal=Trends in Parasitology|date=2004|volume=20|issue=1|pages=13–16|doi=10.1016/j.pt.2003.10.011|pmid=14700584|citeseerx=10.1.1.458.5746}}</ref>

====Liver stage or exo-erythrocytic schizogony====

Entering the hepatocytes, the parasite loses its [[apical complex]] and surface coat and transforms into a [[trophozoite]]. Within the [[parasitophorous vacuole]] of the hepatocyte, it undergoes 13–14 rounds of mitosis which produce a [[Syncytium|syncytial]] cell ([[coenocyte]]) called a schizont. This process is called schizogony. A schizont contains tens of thousands of nuclei. From the surface of the schizont, tens of thousands of haploid (1n) daughter cells called merozoites emerge. The liver stage can produce up to 90,000 merozoites,<ref>{{cite journal|last1=Vaughan|first1=Ashley M.|last2=Kappe|first2=Stefan H.I.|title=Malaria Parasite Liver Infection and Exoerythrocytic Biology|journal=Cold Spring Harbor Perspectives in Medicine|date=2017|volume=7|issue=6|pages=a025486|doi=10.1101/cshperspect.a025486|pmid=28242785|pmc=5453383}}</ref> which are eventually released into the bloodstream in parasite-filled vesicles called merosomes.<ref>{{cite journal|last1=Sturm|first1=A.|title=Manipulation of Host Hepatocytes by the Malaria Parasite for Delivery into Liver Sinusoids|journal=Science|date=2006|volume=313|issue=5791|pages=1287–1290|doi=10.1126/science.1129720|pmid=16888102|bibcode=2006Sci...313.1287S|s2cid=22790721|doi-access=free}}</ref>

====Blood stage or erythrocytic schizogony====
[[Merozoites]] use the [[apicomplexan]] invasion organelles ([[apical complex]], pellicle, and surface coat) to recognize and enter the host erythrocyte ([[red blood cell]]). The merozoites first bind to the erythrocyte in a random orientation. It then reorients such that the apical complex is in proximity to the erythrocyte membrane. The parasite forms a parasitophorous vacuole, to allow for its development inside the [[erythrocyte]].<ref name=cowman>{{cite journal|last1=Cowman|first1=Alan F.|last2=Crabb|first2=Brendan S.|title=Invasion of Red Blood Cells by Malaria Parasites|journal=Cell|date=2006|volume=124|issue=4|pages=755–766|doi=10.1016/j.cell.2006.02.006|pmid=16497586|s2cid=14972823|doi-access=free}}</ref> This infection cycle occurs in a highly synchronous fashion, with roughly all of the parasites throughout the blood in the same stage of development. This precise clocking mechanism is dependent on the human host's own [[circadian rhythm]].<ref name="1.5.2">{{cite web  | title = Malaria eModule – SYNCHRONICITY  | url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5_2.html  | access-date = 2017-06-04  | archive-date = 2007-12-22  | archive-url = https://web.archive.org/web/20071222211547/http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5_2.html  | url-status = dead  }}</ref>

Within the erythrocyte, the parasite metabolism depends on the digestion of [[haemoglobin]]. The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during the blood stage.<ref name="gerald"/>

The parasite can also alter the morphology of the erythrocyte, causing knobs on the erythrocyte membrane. Infected erythrocytes are often sequestered in various human tissues or organs, such as the heart, liver, and brain. This is caused by parasite-derived cell surface proteins being present on the erythrocyte membrane, and it is these proteins that bind to receptors in human cells. Sequestration in the brain causes cerebral malaria, a very severe form of the disease, which increases the victim's likelihood of death.<ref>{{Cite journal|last1=Jensen|first1=Anja Ramstedt|last2=Adams|first2=Yvonne|last3=Hviid|first3=Lars|date=2020|title=Cerebral Plasmodium falciparum malaria: The role of PfEMP1 in its pathogenesis and immunity, and PfEMP1-based vaccines to prevent it|journal=Immunological Reviews|volume=293|issue=1|pages=230–252|doi=10.1111/imr.12807|pmc=6972667|pmid=31562653}}</ref>

=====Trophozoite=====
After invading the erythrocyte, the parasite loses its specific invasion organelles (apical complex and surface coat) and de-differentiates into a round trophozoite located within a parasitophorous vacuole. The trophozoite feeds on the haemoglobin of the erythrocyte, digesting its proteins and converting (by [[biocrystallization]]) the remaining heme into insoluble and chemically inert β-hematin [[crystals]] called haemozoin.<ref>{{cite journal |last1=Pagola |first1=Silvina |last2=Stephens |first2=Peter W. |last3=Bohle |first3=D. Scott |last4=Kosar |first4=Andrew D. |last5=Madsen |first5=Sara K. |title=The structure of malaria pigment β-haematin |journal=Nature |date=March 2000 |volume=404 |issue=6775 |pages=307–310 |doi=10.1038/35005132 |bibcode=2000Natur.404..307P|pmid=10749217|s2cid=4420567}}</ref><ref>{{cite journal |last1=Hempelmann |first1=Ernst |title=Hemozoin Biocrystallization in ''Plasmodium falciparum'' and the antimalarial activity of crystallization inhibitors |journal=Parasitology Research |date=1 March 2007 |volume=100 |issue=4 |pages=671–676 |doi=10.1007/s00436-006-0313-x |language=en |issn=1432-1955 |s2cid=30446678 |pmid=17111179}}</ref> The young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing multiplication.<ref name="1.5">{{cite web | title = Malaria eModule – ASEXUAL ERYTHROCYTIC STAGES | url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5.html | access-date = 2017-06-04 | archive-date = 2007-12-22 | archive-url = https://web.archive.org/web/20071222163324/http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5.html | url-status = dead }}</ref>

=====Schizont=====
At the schizont stage, the parasite replicates its DNA multiple times and multiple mitotic divisions occur asynchronously.<ref>{{cite journal | last1 = Read | first1 = M. | last2 = Sherwin | first2 = T. | last3 = Holloway | first3 = S. P. | last4 = Gull | first4 = K. | last5 = Hyde | first5 = J. E. | year = 1993 | title = Microtubular organization visualized by immunofluorescence microscopy during erythrocytic schizogony in ''Plasmodium falciparum'' and investigation of post-translational modifications of parasite tubulin | journal = Parasitology | volume = 106 | issue = 3| pages = 223–232 | doi=10.1017/s0031182000075041| pmid = 8488059 | s2cid = 24655319 }}</ref><ref>{{cite journal |last1=Arnot |first1=David E. |last2=Ronander |first2=Elena |last3=Bengtsson |first3=Dominique C. |title=The progression of the intra-erythrocytic cell cycle of ''Plasmodium falciparum'' and the role of the centriolar plaques in asynchronous mitotic division during schizogony |journal=International Journal for Parasitology |date=January 2011 |volume=41 |issue=1 |pages=71–80 |doi=10.1016/j.ijpara.2010.07.012 |pmid = 20816844 }}</ref> Cell division and multiplication in the erythrocyte is called erythrocytic schizogony. Each schizont forms 16-18 merozoites.<ref name="1.5"/> The red blood cells are ruptured by the merozoites. The liberated merozoites invade fresh erythrocytes. A free merozoite is in the bloodstream for roughly 60 seconds before it enters another erythrocyte.<ref name=cowman/>

The duration of one complete erythrocytic schizogony is approximately 48 hours. This gives rise to the characteristic clinical manifestations of falciparum malaria, such as fever and chills, corresponding to the synchronous rupture of the infected erythrocytes.<ref name=trampuz03>{{cite journal|last1=Trampuz|first1=Andrej|last2=Jereb|first2=Matjaz|last3=Muzlovic|first3=Igor|last4=Prabhu|first4=Rajesh M|title=Clinical review: Severe malaria|journal=Critical Care|date=2003|volume=7|issue=4|pages=315–23|doi=10.1186/cc2183|pmid=12930555|pmc=270697 |doi-access=free }}</ref>

=====Gametocyte=====
Some merozoites differentiate into sexual forms, male and female [[gametocyte]]s. These gametocytes take roughly 7–15 days to reach full maturity, through the process called gametocytogenesis. These are then taken up by a female ''Anopheles'' mosquito during a blood meal.<ref>{{cite journal|last1=Talman|first1=Arthur M|last2=Domarle|first2=Olivier|last3=McKenzie|first3=F|last4=Ariey|first4=Frédéric|last5=Robert|first5=Vincent|title=Gametocytogenesis: the puberty of ''Plasmodium falciparum''|journal=Malaria Journal|date=2004|volume=3|issue=1|pages=24|doi=10.1186/1475-2875-3-24|pmid=15253774|pmc=497046 |doi-access=free }}</ref>

===Incubation period===
The time of appearance of the symptoms from infection (called [[incubation period]]) is shortest for ''P. falciparum'' among ''Plasmodium'' species. An average incubation period is 11 days,<ref name=trampuz03/> but may range from 9 to 30 days. In isolated cases, prolonged incubation periods as long as 2, 3 or even 8 years have been recorded.<ref>{{cite journal|last1=Bartoloni|first1=A|last2=Zammarchi|first2=L|title=Clinical aspects of uncomplicated and severe malaria|journal=Mediterranean Journal of Hematology and Infectious Diseases|date=2012|volume=4|issue=1|pages=e2012026|doi=10.4084/MJHID.2012.026|pmid=22708041|pmc=3375727}}</ref> Pregnancy and co-infection with [[HIV]] are important conditions for delayed symptoms.<ref>{{cite journal|last1=D'Ortenzio|first1=E|last2=Godineau|first2=N|last3=Fontanet|first3=A|last4=Houze|first4=S|last5=Bouchaud|first5=O|last6=Matheron|first6=S|last7=Le Bras|first7=J|title=Prolonged ''Plasmodium falciparum'' infection in immigrants, Paris|journal=Emerging Infectious Diseases|date=2008|volume=14|issue=2|pages=323–326|doi=10.3201/eid1402.061475|pmid=18258132|pmc=2600192}}</ref> Parasites can be detected from blood samples by the 10th day after infection (pre-patent period).<ref name=trampuz03/>

===In mosquitoes===
Within the mosquito midgut, the female gamete maturation process entails slight morphological changes, becoming more enlarged and spherical. The male gametocyte undergoes a rapid nuclear division within 15 minutes, producing eight [[flagellum|flagellated]] [[microgamete]]s by a process called exflagellation.<ref>{{cite journal|last1=Sinden|first1=R. E.|last2=Canning|first2=E. U.|last3=Bray|first3=R. S.|last4=Smalley|first4=M. E.|title=Gametocyte and Gamete Development in ''Plasmodium falciparum''|journal=Proceedings of the Royal Society B: Biological Sciences|date=1978|volume=201|issue=1145|pages=375–399|doi=10.1098/rspb.1978.0051|pmid=27809|bibcode=1978RSPSB.201..375S|s2cid=27083717}}</ref> The flagellated microgamete fertilizes the female [[macrogamete]] to produce a [[diploid]] cell called a [[zygote]]. The zygote then develops into an [[ookinete]]. The ookinete is a motile cell, capable of invading other organs of the mosquito. It traverses the [[peritrophic membrane]] of the mosquito midgut and crosses the midgut epithelium. Once through the epithelium, the ookinete enters the [[basal lamina]] and settles into an immotile [[oocyst]]. For several days, the oocyst undergoes 10 to 11 rounds of cell division to create a [[syncytium|syncytial]] cell ([[sporoblast]]) containing thousands of nuclei. Meiosis takes place inside the sporoblast to produce over 3,000 haploid daughter cells called sporozoites on the surface of the mother cell.<ref>{{cite journal|last1=Rungsiwongse|first1=Jarasporn|last2=Rosenberg|first2=Ronald|title=The Number of Sporozoites Produced by Individual Malaria Oocysts|journal=The American Journal of Tropical Medicine and Hygiene|date=1991|volume=45|issue=5|pages=574–577|doi=10.4269/ajtmh.1991.45.574|pmid=1951866}}</ref> Immature sporozoites break through the oocyst wall into the [[haemolymph]]. They migrate to the mosquito salivary glands where they undergo further development and become infective to humans.<ref name="gerald"/>

'''Effects of plant secondary metabolites on ''P. falciparum'''''

Mosquitoes are known to forage on plant nectar for sugar meal, the primary source of energy and nutrients for their survival and other biological process such as host seeking for blood or searching for oviposition sites.<ref>{{Cite journal |last=Foster |first=W. A. |date=1995-01-01 |title=Mosquito Sugar Feeding and Reproductive Energetics |url=http://ento.annualreviews.org/cgi/doi/10.1146/annurev.ento.40.1.443 |journal=Annual Review of Entomology |volume=40 |issue=1 |pages=443–474 |doi=10.1146/annurev.ento.40.1.443|pmid=7810991 |url-access=subscription }}</ref> Researchers have recently discovered that mosquitoes are very selective about their sugar meal sources.<ref>{{Cite journal |last1=Nyasembe |first1=Vincent O. |last2=Teal |first2=Peter E.A. |last3=Sawa |first3=Patrick |last4=Tumlinson |first4=James H. |last5=Borgemeister |first5=Christian |last6=Torto |first6=Baldwyn |date=January 2014 |title=Plasmodium falciparum Infection Increases Anopheles gambiae Attraction to Nectar Sources and Sugar Uptake |journal=Current Biology |language=en |volume=24 |issue=2 |pages=217–221 |doi=10.1016/j.cub.2013.12.022|pmid=24412210 |pmc=3935215 |bibcode=2014CBio...24..217N }}</ref> For example ''Anopheles'' mosquitos prefer some plants over others, specifically those containing compounds that hinder the development and survival of malaria parasites inside the mosquito.<ref>{{Cite journal |last1=Hien |first1=Domonbabele F. d. S. |last2=Dabiré |first2=Kounbobr R. |last3=Roche |first3=Benjamin |last4=Diabaté |first4=Abdoulaye |last5=Yerbanga |first5=Rakiswende S. |last6=Cohuet |first6=Anna |last7=Yameogo |first7=Bienvenue K. |last8=Gouagna |first8=Louis-Clément |last9=Hopkins |first9=Richard J. |last10=Ouedraogo |first10=Georges A. |last11=Simard |first11=Frédéric |last12=Ouedraogo |first12=Jean-Bosco |last13=Ignell |first13=Rickard |last14=Lefevre |first14=Thierry |date=2016-08-04 |editor-last=Vernick |editor-first=Kenneth D |title=Plant-Mediated Effects on Mosquito Capacity to Transmit Human Malaria |journal=PLOS Pathogens |language=en |volume=12 |issue=8 |pages=e1005773 |doi=10.1371/journal.ppat.1005773 |doi-access=free |issn=1553-7374 |pmc=4973987 |pmid=27490374}}</ref> This discovery offers an opportunity to look into what could be playing a role in these behavior changes in mosquitoes and also find out what they ingest when they foraged on the selected plants. In other studies, it has been shown that sources of sugars and some secondary metabolites e.g. ricinine, have contrasting effects on mosquito capacity to transmit the parasites malaria.<ref>{{Cite journal |last1=Hien |first1=Domonbabele F. D. S. |last2=Paré |first2=Prisca S. L. |last3=Cooper |first3=Amanda |last4=Koama |first4=Benjamin K. |last5=Guissou |first5=Edwige |last6=Yaméogo |first6=Koudraogo B. |last7=Yerbanga |first7=Rakiswendé S. |last8=Farrell |first8=Iain W. |last9=Ouédraogo |first9=Jean B. |last10=Gnankiné |first10=Olivier |last11=Ignell |first11=Rickard |last12=Cohuet |first12=Anna |last13=Dabiré |first13=Roch K. |last14=Stevenson |first14=Philip C. |last15=Lefèvre |first15=Thierry |date=December 2021 |title=Contrasting effects of the alkaloid ricinine on the capacity of Anopheles gambiae and Anopheles coluzzii to transmit Plasmodium falciparum |journal=Parasites & Vectors |language=en |volume=14 |issue=1 |page=479 |doi=10.1186/s13071-021-04992-z |doi-access=free |issn=1756-3305 |pmc=8444468 |pmid=34526119}}</ref>

===Meiosis===

''Plasmodium falciparum'' is [[ploidy|haploid]] (one set of chromosomes) during its reproductive stages in human blood and liver. When a mosquito takes a blood meal from a [[plasmodium]] infected human host, this meal may include haploid micro[[gamete]]s and macro[[gamete]]s. Such gametes can fuse within the mosquito to form a diploid (2N) plasmodium [[zygote]], the only diploid stage in the life cycle of these parasites.<ref name = Guttery2023>{{cite journal |last1=Guttery |first1=David S. |last2=Zeeshan |first2=Mohammad |last3=Holder |first3=Anthony A. |last4=Tromer |first4=Eelco C. |last5=Tewari |first5=Rita |title=Meiosis in Plasmodium: how does it work? |journal=Trends in Parasitology |date=October 2023 |volume=39 |issue=10 |pages=812–821 |doi=10.1016/j.pt.2023.07.002}}</ref> The zygote can undergo another round of [[chromosome]] replication to form an ookinete (4N) (see Figure: Life cycle of plasmodium). The ookinete that differentiates from the zygote is a highly mobile stage that invades the mosquito midgut. The ookinetes can undergo [[meiosis]] involving two meiotic divisions leading to the release of haploid sporozoites (see Figure).<ref name = Guttery2023/> The sporozoite is an elongated crescent-shaped invasive stage. These sporozoites may migrate to the mosquito’s salivary glands and can enter a human host when the mosquito takes a blood meal. The sporozoite then can move to the human host liver and infect [[hepatocyte]]s. 

The profile of genes encoded by plasmodium that are employed in meiosis has some overlap with the profile of genes employed in meiosis in other more well-studied organisms, but is more divergent and is lacking some components of the meiotic process found in other organisms.<ref name = Guttery2023/> During plasmodium meiosis, [[homologous recombination|recombination]] occurs between homologous chromosomes as in other organisms.

==Interaction with human immune system==
===Immune response===
A single anopheline mosquito can transmit hundreds of ''P. falciparum'' sporozoites in a single bite under experimental conditions, but, in nature, the number is generally less than 80.<ref>{{cite journal|last1=Beier|first1=JC|last2=Onyango|first2=FK|last3=Koros|first3=JK|last4=Ramadhan|first4=M|last5=Ogwang|first5=R|last6=Wirtz|first6=RA|last7=Koech|first7=DK|last8=Roberts|first8=CR|title=Quantitation of malaria sporozoites transmitted in vitro during salivation by wild Afrotropical Anopheles|journal=Medical and Veterinary Entomology|date=1991|volume=5|issue=1|pages=71–9|doi=10.1111/j.1365-2915.1991.tb00523.x|pmid=1768903|s2cid=27449694}}</ref> The sporozoites do not enter the bloodstream directly, but rather remain in the skin for two to three hours. About 15–20% of the sporozoites enter the lymphatic system, where they activate [[dendritic cells]], which send them for destruction by T lymphocytes ([[Cytotoxic T cell|CD8+ T cells]]). At 48 hours after infection, ''Plasmodium''-specific CD8+ T cells can be detected in the [[lymph nodes]] connected to the skin cells.<ref name=chakravarty>{{cite journal|last1=Chakravarty|first1=Sumana|last2=Cockburn|first2=Ian A|last3=Kuk|first3=Salih|last4=Overstreet|first4=Michael G|last5=Sacci|first5=John B|last6=Zavala|first6=Fidel|title=CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes|journal=Nature Medicine|date=2007|volume=13|issue=9|pages=1035–1041|doi=10.1038/nm1628|pmid=17704784|s2cid=17601147|doi-access=free}}</ref> Most of the sporozoites remaining in the skin tissue are subsequently killed by the [[innate immune system]]. The sporozoite glycoprotein specifically activates [[mast cells]]. The mast cells then produce [[Cytokine|signaling molecules]] such as [[TNFα]] and MIP-2, which activate cell eaters (professional phagocytes) such as [[neutrophils]] and [[macrophages]].<ref>{{cite journal|last1=Hopp|first1=Christine S.|last2=Sinnis|first2=Photini|title=The innate and adaptive response to mosquito saliva and Plasmodium sporozoites in the skin|journal=Annals of the New York Academy of Sciences|date=2015|volume=1342|issue=1|pages=37–43|doi=10.1111/nyas.12661|pmid=25694058|pmc=4405444|bibcode=2015NYASA1342...37H}}</ref>

Only a small number (0.5-5%) of sporozoites enter the bloodstream into the liver. In the liver, the activated CD8+ T cells from the lymph bind the sporozoites through the [[circumsporozoite protein]] (CSP).<ref name=chakravarty/> [[Antigen presentation]] by dendritic cells in the skin tissue to T cells is also a crucial process. From this stage onward, the parasites produce different proteins that help suppress communication of the immune cells.<ref>{{cite journal|last1=Gomes|first1=Pollyanna S.|last2=Bhardwaj|first2=Jyoti|last3=Rivera-Correa|first3=Juan|last4=Freire-De-Lima|first4=Celio G.|last5=Morrot|first5=Alexandre|title=Immune Escape Strategies of Malaria Parasites|journal=Frontiers in Microbiology|date=2016|volume=7|page=e1617|doi=10.3389/fmicb.2016.01617|pmid=27799922|pmc=5066453|doi-access=free}}</ref> Even at the height of the infection, when red blood cells (RBCs) are ruptured, the immune signals are not strong enough to activate macrophages or [[natural killer cells]].<ref>{{cite journal|last1=Artavanis-Tsakonas|first1=K|last2=Tongren|first2=JE|last3=Riley|first3=EM|title=The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology|journal=Clinical and Experimental Immunology|date=August 2003|volume=133|issue=2|pages=145–152|doi=10.1046/j.1365-2249.2003.02174.x|pmid=12869017|pmc=1808775}}{{open access}}</ref>

===Immune system evasion===
Although ''P. falciparum'' is easily recognized by the human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens.<ref name=florens>{{cite journal|last1=Florens|first1=Laurence|last2=Washburn|first2=Michael P.|last3=Raine|first3=J. Dale|last4=Anthony|first4=Robert M.|last5=Grainger|first5=Munira|last6=Haynes|first6=J. David|last7=Moch|first7=J. Kathleen|last8=Muster|first8=Nemone|last9=Sacci|first9=John B.|last10=Tabb|first10=David L.|last11=Witney|first11=Adam A.|last12=Wolters|first12=Dirk|last13=Wu|first13=Yimin|last14=Gardner|first14=Malcolm J.|last15=Holder|first15=Anthony A.|last16=Sinden|first16=Robert E.|last17=Yates|first17=John R.|last18=Carucci|first18=Daniel J.|title=A proteomic view of the ''Plasmodium falciparum'' life cycle|journal=Nature|date=3 October 2002|volume=419|issue=6906|pages=520–526|doi=10.1038/nature01107|pmid=12368866|display-authors=8|bibcode=2002Natur.419..520F|s2cid=4412848|doi-access=free}}</ref> The initial infective stage sporozoites produce circumsporozoite protein (CSP), which binds to hepatocytes.<ref>{{cite journal|last1=Cerami|first1=Carla|last2=Frevert|first2=Ute|last3=Sinnis|first3=Photini|last4=Takacs|first4=Bela|last5=Clavijo|first5=Pedro|last6=Santos|first6=Manuel J.|last7=Nussenzweig|first7=Victor|title=The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of ''Plasmodium falciparum'' sporozoites|journal=Cell|date=1992|volume=70|issue=6|pages=1021–1033|doi=10.1016/0092-8674(92)90251-7|pmid=1326407|s2cid=8825913}}</ref> Binding to and entering into the hepatocytes is aided by thrombospondin-related anonymous protein (TRAP).<ref>{{cite journal|last1=Baldacci|first1=Patricia|last2=Ménard|first2=Robert|title=The elusive malaria sporozoite in the mammalian host|journal=Molecular Microbiology|date=2004|volume=54|issue=2|pages=298–306|doi=10.1111/j.1365-2958.2004.04275.x|pmid=15469504|s2cid=30488807|doi-access=free}}</ref> TRAP and other secretory proteins (including sporozoite microneme protein essential for cell traversal 1, SPECT1 and SPECT2) from microneme allow the sporozoite to move through the blood, avoiding immune cells and penetrating hepatocytes.<ref name="vaughan">{{cite journal|last1=Vaughan|first1=Ashley M.|last2=Aly|first2=Ahmed S.I.|last3=Kappe|first3=Stefan H.I.|title=Malaria Parasite Pre-Erythrocytic Stage Infection: Gliding and Hiding|journal=Cell Host & Microbe|date=2008|volume=4|issue=3|pages=209–218|doi=10.1016/j.chom.2008.08.010|pmid=18779047|pmc=2610487}}</ref>

During erythrocyte invasion, merozoites release merozoite cap protein-1 (MCP1), apical membrane antigen 1 (AMA1), erythrocyte-binding antigens (EBA), myosin A tail domain interacting protein (MTIP), and [[merozoite surface protein]]s (MSPs).<ref name=florens/> Of these MSPs, MSP1 and MSP2 are primarily responsible for avoiding immune cells.<ref>{{cite journal|last1=Satchwell|first1=T. J.|title=Erythrocyte invasion receptors for ''Plasmodium falciparum'': new and old|journal=Transfusion Medicine|date=2016|volume=26|issue=2|pages=77–88|doi=10.1111/tme.12280|pmid=26862042|hdl=1983/2945cc98-49e8-4c37-a392-88e35fab588c|s2cid=7811400|url=https://research-information.bristol.ac.uk/en/publications/erythrocyte-invasion-receptors-for-plasmodium-falciparum(2945cc98-49e8-4c37-a392-88e35fab588c).html|hdl-access=free}}</ref> The virulence of ''P. falciparum'' is mediated by erythrocyte membrane proteins, which are produced by the schizonts and trophozoites inside the erythrocytes and are displayed on the erythrocyte membrane. [[PfEMP1]] is the most important, capable of acting as both an antigen and an adhesion molecule.<ref>{{cite journal|last1=Lalchhandama|first1=Kholhring|title=''Plasmodium falciparum'' erythrocyte membrane protein 1|journal=WikiJournal of Medicine|date=2017|volume=4|issue=1|pages=1–8|doi=10.15347/wjm/2017.004|doi-access=free}}</ref>

== Pathogenicity ==
{{Main|Malaria}}
The clinical symptoms of falciparum malaria are produced by the rupture and destruction of erythrocytes by the merozoites. High fever, called paroxysm, is the most basic indication. The fever has a characteristic cycle of hot stage, cold stage, and sweating stages.<ref name=":1">{{Citation|last1=Crutcher|first1=James M.|title=Malaria|date=1996|url=http://www.ncbi.nlm.nih.gov/books/NBK8584/|work=Medical Microbiology|editor-last=Baron|editor-first=Samuel|edition=4th|place=Galveston (TX)|publisher=University of Texas Medical Branch at Galveston|isbn=978-0-9631172-1-2|pmid=21413352|access-date=2022-02-01|last2=Hoffman|first2=Stephen L.}}</ref> Since each erythrocytic schizogony takes a cycle of 48 hours, i.e., two days, the febrile symptom appears every third day. This is the reason the infection is classically named tertian malignant fever (tertian, a derivative of a Latin word that means "third").<ref>{{Cite journal|last=Buchanan|first=Andrew|date=1901|title=Malignant Tertian Fever|journal=The Indian Medical Gazette|volume=36|issue=7|pages=256–258|issn=0019-5863|pmc=5164271|pmid=29004267}}</ref><ref>{{Cite journal|last1=Hemmer|first1=C. J.|last2=Loebermann|first2=M.|last3=Reisinger|first3=E. C.|date=2016|title=Fever after travel to tropical regions: Malaria and other emergencies|journal=Notfall & Rettungsmedizin|volume=19|issue=4|pages=263–268|doi=10.1007/s10049-016-0176-3|issn=1434-6222|pmc=7101662|pmid=32288635}}</ref> The most common symptoms are [[fever]] (>92% of cases), [[chills]] (79%), [[headaches]] (70%), and [[sweating]] (64%). [[Dizziness]], [[malaise]], [[myalgia|muscle pain]], [[abdominal pain]], [[nausea]], [[vomiting]], mild [[diarrhea]], and [[dry cough]] are also generally associated. [[Tachycardia|High heartrate]], [[jaundice]], [[pallor]], [[orthostatic hypotension]], [[hepatomegaly|enlarged liver]], and [[splenomegaly|enlarged spleen]] are also diagnosed.<ref name="trampuz03" />

The insoluble β-hematin crystal, [[Hemozoin|haemozoin]], produced from the digestion of haemoglobin of the RBCs is the main agent that affects body organs. Acting as a blood toxin, haemozoin-containing RBCs cannot be attacked by phagocytes during the immune response to malaria.<ref>{{Cite journal|last1=Corbett|first1=Yolanda|last2=Parapini|first2=Silvia|last3=Perego|first3=Federica|last4=Messina|first4=Valeria|last5=Delbue|first5=Serena|last6=Misiano|first6=Paola|last7=Falchi|first7=Mario|last8=Silvestrini|first8=Francesco|last9=Taramelli|first9=Donatella|last10=Basilico|first10=Nicoletta|last11=D'Alessandro|first11=Sarah|date=2021|title=Phagocytosis and activation of bone marrow-derived macrophages by ''Plasmodium falciparum'' gametocytes|journal=Malaria Journal|volume=20|issue=1|pages=81|doi=10.1186/s12936-021-03589-2|issn=1475-2875|pmc=7874634|pmid=33568138 |doi-access=free }}</ref> The phagocytes can ingest free haemozoins liberated after the rupture of RBCs by which they are induced to initiate chains of [[inflammatory reaction]] that results in increased fever.<ref>{{Cite journal|last1=Coronado|first1=Lorena M.|last2=Nadovich|first2=Christopher T.|last3=Spadafora|first3=Carmenza|date=2014|title=Malarial Hemozoin: From target to tool|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|volume=1840|issue=6|pages=2032–2041|doi=10.1016/j.bbagen.2014.02.009|issn=0006-3002|pmc=4049529|pmid=24556123}}</ref><ref>{{Cite journal|last1=Tyberghein|first1=Ariane|last2=Deroost|first2=Katrien|last3=Schwarzer|first3=Evelin|last4=Arese|first4=Paolo|last5=Van den Steen|first5=Philippe E.|date=2014|title=Immunopathological effects of malaria pigment or hemozoin and other crystals|journal=BioFactors|volume=40|issue=1|pages=59–78|doi=10.1002/biof.1119|issn=1872-8081|pmid=23907956|s2cid=45386035|doi-access=free}}</ref> It is the haemozoin that is deposited in body organs such as the spleen and liver, as well as in kidneys and lungs, to cause their enlargement and discolouration.<ref>{{Cite journal|last1=Deroost|first1=Katrien|last2=Lays|first2=Natacha|last3=Noppen|first3=Sam|last4=Martens|first4=Erik|last5=Opdenakker|first5=Ghislain|last6=Van den Steen|first6=Philippe E.|date=2012|title=Improved methods for haemozoin quantification in tissues yield organ-and parasite-specific information in malaria-infected mice|journal=Malaria Journal|volume=11|pages=166|doi=10.1186/1475-2875-11-166|issn=1475-2875|pmc=3473299|pmid=22583751 |doi-access=free }}</ref><ref>{{Cite journal|last1=Pek|first1=Rini H.|last2=Yuan|first2=Xiaojing|last3=Rietzschel|first3=Nicole|last4=Zhang|first4=Jianbing|last5=Jackson|first5=Laurie|last6=Nishibori|first6=Eiji|last7=Ribeiro|first7=Ana|last8=Simmons|first8=William|last9=Jagadeesh|first9=Jaya|last10=Sugimoto|first10=Hiroshi|last11=Alam|first11=Md Zahidul|date=2019|title=Hemozoin produced by mammals confers heme tolerance|journal=eLife|volume=8|pages=e49503|doi=10.7554/eLife.49503|issn=2050-084X|pmc=6773446|pmid=31571584 |doi-access=free }}</ref> Because of this, haemozoin is also known as malarial pigment.<ref>{{Cite journal|last1=Olivier|first1=Martin|last2=Van Den Ham|first2=Kristin|last3=Shio|first3=Marina Tiemi|last4=Kassa|first4=Fikregabrail Aberra|last5=Fougeray|first5=Sophie|date=2014|title=Malarial pigment hemozoin and the innate inflammatory response|journal=Frontiers in Immunology|volume=5|pages=25|doi=10.3389/fimmu.2014.00025|issn=1664-3224|pmc=3913902|pmid=24550911|doi-access=free}}</ref><ref>{{Cite journal|last1=Shio|first1=Marina T.|last2=Kassa|first2=Fikregabrail A.|last3=Bellemare|first3=Marie-Josée|last4=Olivier|first4=Martin|date=2010|title=Innate inflammatory response to the malarial pigment hemozoin|url=https://pubmed.ncbi.nlm.nih.gov/20637890|journal=Microbes and Infection|volume=12|issue=12–13|pages=889–899|doi=10.1016/j.micinf.2010.07.001|issn=1769-714X|pmid=20637890}}</ref>

Unlike other forms of malaria, which show regular periodicity of fever, falciparum, though exhibiting a 48-hour cycle, usually presents as irregular bouts of fever''.'' This difference is due to the ability of ''P. falciparum'' merozoites to invade a large number of RBCs sequentially without coordinated intervals, which is not seen in other malarial parasites.<ref name=":1"/> ''P. falciparum'' is therefore responsible for almost all severe human illnesses and deaths due to malaria, in a condition called pernicious or complicated or severe malaria. Complicated malaria occurs more commonly in children under age 5,<ref name="trampuz03" /> and sometimes in pregnant women (a condition specifically called [[pregnancy-associated malaria]]).<ref name="moya14">{{cite journal|last1=Moya-Alvarez|first1=Violeta|last2=Abellana|first2=Rosa|last3=Cot|first3=Michel|date=2014|title=Pregnancy-associated malaria and malaria in infants: an old problem with present consequences|journal=Malaria Journal|volume=13|issue=1|pages=271|doi=10.1186/1475-2875-13-271|pmc=4113781|pmid=25015559 |doi-access=free }}</ref> Women become susceptible to severe malaria during their first pregnancy. Susceptibility to severe malaria is reduced in subsequent pregnancies due to increased antibody levels against variant surface [[antigens]] that appear on infected erythrocytes.<ref>{{cite journal|last1=Kourtis|first1=Athena P.|last2=Read|first2=Jennifer S.|last3=Jamieson|first3=Denise J.|date=2014|title=Pregnancy and Infection|journal=New England Journal of Medicine|volume=370|issue=23|pages=2211–2218|doi=10.1056/NEJMra1213566|pmc=4459512|pmid=24897084}}</ref> But increased immunity in the mother increases susceptibility to malaria in newborn babies.<ref name="moya14" />

''P. falciparum'' works via sequestration, a process by which group of infected RBCs are clustered, which is not exhibited by any other species of malarial parasites.<ref>{{Cite journal|last1=Tembo|first1=Dumizulu L.|last2=Nyoni|first2=Benjamin|last3=Murikoli|first3=Rekah V.|last4=Mukaka|first4=Mavuto|last5=Milner|first5=Danny A.|last6=Berriman|first6=Matthew|last7=Rogerson|first7=Stephen J.|last8=Taylor|first8=Terrie E.|last9=Molyneux|first9=Malcolm E.|last10=Mandala|first10=Wilson L.|last11=Craig|first11=Alister G.|date=2014|title=Differential PfEMP1 expression is associated with cerebral malaria pathology|journal=PLOS Pathogens|volume=10|issue=12|pages=e1004537|doi=10.1371/journal.ppat.1004537|pmc=4256257|pmid=25473835 |doi-access=free }}</ref> The mature schizonts change the surface properties of infected erythrocytes, causing them to stick to blood vessel walls (cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, such as the brain in [[cerebral malaria]].<ref>{{cite journal |last1=Dondorp |first1=Arjen M. |last2=Pongponratn |first2=Emsri |last3=White |first3=Nicholas J. |title=Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology |journal=Acta Tropica |date=February 2004 |volume=89 |issue=3 |pages=309–317 |doi=10.1016/j.actatropica.2003.10.004 |pmid=14744557}}</ref>

Cerebral malaria is the most dangerous condition of any malarial infection and the most severe form of [[neurological disorders]]. According to the WHO definition, the clinical symptom is indicated by coma and diagnosis by a high level of merozoites in the peripheral blood samples.<ref>{{Cite journal|last=Anonymous|date=2000|title=Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster|url=https://pubmed.ncbi.nlm.nih.gov/11103309/|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|volume=94|issue=Suppl 1 |pages=S1–90|issn=0035-9203|pmid=11103309}}</ref><ref>{{Cite journal|last1=Omar|first1=Mohamed|last2=Marchionni|first2=Luigi|last3=Häcker|first3=Georg|last4=Badr|first4=Mohamed Tarek|date=2021|title=Host Blood Gene Signatures Can Detect the Progression to Severe and Cerebral Malaria|journal=Frontiers in Cellular and Infection Microbiology|volume=11|pages=743616|doi=10.3389/fcimb.2021.743616|issn=2235-2988|pmc=8569259|pmid=34746025|doi-access=free}}</ref> It is the deadliest form of malaria, and to it are attributed to 0.2 million to over a million annual deaths throughout the ages. Most deaths are of children of below 5 years of age.<ref>{{Cite journal|last1=Murphy|first1=S. C.|last2=Breman|first2=J. G.|date=2001|title=Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy|url=https://www.ncbi.nlm.nih.gov/books/NBK2621/|journal=The American Journal of Tropical Medicine and Hygiene|volume=64|issue=1-2 Suppl|pages=57–67|doi=10.4269/ajtmh.2001.64.57|pmid=11425178|s2cid=847217 |doi-access=free}}</ref><ref>{{Cite journal|last=Breman|first=J. G.|date=2001|title=The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden|journal=The American Journal of Tropical Medicine and Hygiene|volume=64|issue=1-2 Suppl|pages=1–11|doi=10.4269/ajtmh.2001.64.1|issn=0002-9637|pmid=11425172|doi-access=free}}</ref> It occurs when the merozoites invade the brain and cause brain damage of varying degrees. Death is caused by oxygen deprivation (hypoxia) due to inflammatory cytokine production and vascular leakage induced by the merozoites.<ref>{{Cite journal|last1=Luzolo|first1=Ange Landela|last2=Ngoyi|first2=Dieudonné Mumba|date=2019|title=Cerebral malaria|url=https://pubmed.ncbi.nlm.nih.gov/30658131|journal=Brain Research Bulletin|volume=145|pages=53–58|doi=10.1016/j.brainresbull.2019.01.010|issn=1873-2747|pmid=30658131|s2cid=58560596}}</ref> Among the surviving individuals, persistent medical conditions such as neurological impairment, [[intellectual disability]], and [[Emotional and behavioral disorders|behavioural problems]] exist. Among them, [[epilepsy]] is the most common condition, and cerebral malaria is the leading cause of acquired epilepsy among African children.<ref>{{Cite journal|last1=Idro|first1=Richard|last2=Marsh|first2=Kevin|last3=John|first3=Chandy C|last4=Newton|first4=Charles RJ|date=2010|title=Cerebral Malaria; Mechanisms Of Brain Injury And Strategies For Improved Neuro-Cognitive Outcome|journal=Pediatric Research|volume=68|issue=4|pages=267–274|doi=10.1203/PDR.0b013e3181eee738|issn=0031-3998|pmc=3056312|pmid=20606600}}</ref>

The reappearance of falciparum symptom, a phenomenon called recrudescence, is often seen in survivors.<ref>{{Cite journal|last=Shanks|first=G. Dennis|date=2015|title=Historical review: does stress provoke ''Plasmodium falciparum'' recrudescence?|url=https://pubmed.ncbi.nlm.nih.gov/25918217|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|volume=109|issue=6|pages=360–365|doi=10.1093/trstmh/trv032|issn=1878-3503|pmid=25918217}}</ref> Recrudescence can occur even after successful antimalarial medication.<ref>{{Cite journal|last1=Teuscher|first1=Franka|last2=Gatton|first2=Michelle L.|last3=Chen|first3=Nanhua|last4=Peters|first4=Jennifer|last5=Kyle|first5=Dennis E.|last6=Cheng|first6=Qin|date=2010|title=Artemisinin-induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure|journal=The Journal of Infectious Diseases|volume=202|issue=9|pages=1362–1368|doi=10.1086/656476|issn=1537-6613|pmc=2949454|pmid=20863228}}</ref><ref>{{Cite journal|last=WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group|date=2015|title=Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data|journal=BMC Medicine|volume=13|pages=227|doi=10.1186/s12916-015-0456-7|issn=1741-7015|pmc=4574542|pmid=26381375 |doi-access=free }}</ref> It may take a few months or even several years. In some individuals, it takes as long as three years.<ref>{{Cite journal|last1=Al Hammadi|first1=Ahmed|last2=Mitchell|first2=Michael|last3=Abraham|first3=George M.|last4=Wang|first4=Jennifer P.|date=2017|title=Recrudescence of Plasmodium falciparum in a Primigravida After Nearly 3 Years of Latency|journal=The American Journal of Tropical Medicine and Hygiene|volume=96|issue=3|pages=642–644|doi=10.4269/ajtmh.16-0803|issn=1476-1645|pmc=5361538|pmid=28044045}}</ref> In isolated cases, the duration can reach or exceed 10 years.<ref>{{Cite journal|last1=Salas-Coronas|first1=Joaquín|last2=Soriano-Pérez|first2=Manuel Jesús|last3=Lozano-Serrano|first3=Ana B.|last4=Pérez-Moyano|first4=Rosario|last5=Porrino-Herrera|first5=Carmen|last6=Cabezas-Fernández|first6=María Teresa|date=2017|title=Symptomatic Falciparum Malaria After Living in a Nonendemic Area for 10 Years: Recrudescence or Indigenous Transmission?|journal=The American Journal of Tropical Medicine and Hygiene|volume=96|issue=6|pages=1427–1429|doi=10.4269/ajtmh.17-0031|issn=1476-1645|pmc=5462582|pmid=28719260}}</ref><ref>{{Cite journal|last1=Ismail|first1=Arif|last2=Auclair|first2=Francois|last3=McCarthy|first3=Anne E.|date=2020|title=Recrudescence of chronic Plasmodium falciparum malaria 13 years after exposure|url=https://pubmed.ncbi.nlm.nih.gov/31712180/|journal=Travel Medicine and Infectious Disease|volume=33|pages=101518|doi=10.1016/j.tmaid.2019.101518|issn=1873-0442|pmid=31712180|s2cid=207949553}}</ref> It is also a common incident among pregnant women.<ref>{{Cite journal|last1=Mayor|first1=Alfredo|last2=Serra-Casas|first2=Elisa|last3=Bardají|first3=Azucena|last4=Sanz|first4=Sergi|last5=Puyol|first5=Laura|last6=Cisteró|first6=Pau|last7=Sigauque|first7=Betuel|last8=Mandomando|first8=Inacio|last9=Aponte|first9=John J.|last10=Alonso|first10=Pedro L.|last11=Menéndez|first11=Clara|date=2009|title=Sub-microscopic infections and long-term recrudescence of Plasmodium falciparum in Mozambican pregnant women|journal=Malaria Journal|volume=8|pages=9|doi=10.1186/1475-2875-8-9|issn=1475-2875|pmc=2633011|pmid=19134201 |doi-access=free }}</ref><ref>{{Cite journal|last1=Laochan|first1=Natthapon|last2=Zaloumis|first2=Sophie G.|last3=Imwong|first3=Mallika|last4=Lek-Uthai|first4=Usa|last5=Brockman|first5=Alan|last6=Sriprawat|first6=Kanlaya|last7=Wiladphaingern|first7=Jacher|last8=White|first8=Nicholas J.|last9=Nosten|first9=François|last10=McGready|first10=Rose|date=2015|title=Intervals to Plasmodium falciparum recurrence after anti-malarial treatment in pregnancy: a longitudinal prospective cohort|journal=Malaria Journal|volume=14|pages=221|doi=10.1186/s12936-015-0745-9|issn=1475-2875|pmc=4449611|pmid=26017553 |doi-access=free }}</ref>

==Distribution and epidemiology==
[[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, showing ''P. falciparum'' (red) predominating in areas including Africa and the Caribbean.<ref name="Tatem2017">{{cite journal |last1=Tatem |first1=Andrew J |last2=Jia |first2=Peng |last3=Ordanovich |first3=Dariya |last4=Falkner |first4=Michael |last5=Huang |first5=Zhuojie |last6=Howes |first6=Rosalind |last7=Hay |first7=Simon I |last8=Gething |first8=Peter W |last9=Smith |first9=David L |title=The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics |journal=The Lancet Infectious Diseases |date=January 2017 |volume=17 |issue=1 |pages=98–107 |doi=10.1016/S1473-3099(16)30326-7 | pmid=27777030 | pmc=5392593 | bibcode=2017LanID..17...98T}}</ref>]]
[[File:Modelling-the-global-constraints-of-temperature-on-transmission-of-Plasmodium-falciparum-and-P.-1756-3305-4-92-S3.ogv|thumb|The Z(T) normalized index of temperature suitability for ''P. falciparum'' displayed by week across an average year.]]
''P. falciparum'' is endemic in 84 countries,<ref name="who2022">{{cite book |last1=WHO |url=https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024 |title=World Malaria Report 2024 |date=2024 |publisher=World Health Organization |isbn=978-92-4-010444-0 |location=Switzerland}}</ref> and is found in all continents except Europe. Historically, it was present in most European countries, but improved health conditions led to the disappearance in the early 20th century.<ref>{{Cite journal|last=Majori|first=Giancarlo|date=2012|title=Short History of Malaria and Its Eradication in Italy With Short Notes on the Fight Against the Infection in the Mediterranean Basin|journal=Mediterranean Journal of Hematology and Infectious Diseases|volume=4|issue=1|pages=e2012016|doi=10.4084/MJHID.2012.016|issn=2035-3006|pmc=3340992|pmid=22550561}}</ref> The only European country where it used to be historically prevalent, and from where we got the name malaria, Italy had been declared malaria-eradicated country. In 1947, the Italian government launched the National Malaria Eradication Program, and following, an anti-mosquito campaign was implemented using DDT.<ref>{{Cite journal|last1=Kitron|first1=U.|last2=Spielman|first2=A.|date=1989|title=Suppression of transmission of malaria through source reduction: antianopheline measures applied in Israel, the United States, and Italy|url=https://pubmed.ncbi.nlm.nih.gov/2665000/|journal=Reviews of Infectious Diseases|volume=11|issue=3|pages=391–406|doi=10.1093/clinids/11.3.391|issn=0162-0886|pmid=2665000}}</ref> The WHO declared Italy free of malaria in 1970.<ref>{{Cite journal|last1=Martini|first1=Mariano|last2=Angheben|first2=Andrea|last3=Riccardi|first3=Niccolò|last4=Orsini|first4=Davide|date=2021|title=Fifty years after the eradication of Malaria in Italy. The long pathway toward this great goal and the current health risks of imported malaria|journal=Pathogens and Global Health|volume=115|issue=4|pages=215–223|doi=10.1080/20477724.2021.1894394|issn=2047-7732|pmc=8168761|pmid=33734023}}</ref>

There were an estimated 263 million cases of malaria worldwide in 2023, resulting in an estimated 597,000 deaths.<ref name="who2022" /> The infection is most prevalent in Africa, where 95% of malaria deaths occur.<ref name="who2022" /> Children under five years of age are most affected, and 67% of malaria deaths occurred in this age group. 80% of the infection is found in Sub-Saharan Africa, 7% in South-East Asia, and 2% in the Eastern Mediterranean. Nigeria has the highest incidence, with 27% of the total global cases. Outside Africa, India has the highest incidence, with 4.5% of the global burden. Europe is regarded as a malaria-free region. Historically, the parasite and its disease had been most well-known in Europe. But medical programmes since the early 20th century, such as insecticide spraying, drug therapy, and environmental engineering, resulted in complete eradication in the 1970s.<ref>{{cite journal|last1=Piperaki|first1=E.T.|last2=Daikos|first2=G.L.|title=Malaria in Europe: emerging threat or minor nuisance?|journal=Clinical Microbiology and Infection|date=2016|volume=22|issue=6|pages=487–493|doi=10.1016/j.cmi.2016.04.023|pmid=27172807|doi-access=free}}</ref> It is estimated that approximately 2.4 billion people are at constant risk of infection.<ref>{{cite journal|last1=Bousema|first1=T.|last2=Drakeley|first2=C.|title=Epidemiology and Infectivity of ''Plasmodium falciparum'' and ''Plasmodium vivax'' Gametocytes in Relation to Malaria Control and Elimination|journal=Clinical Microbiology Reviews|date=2011|volume=24|issue=2|pages=377–410|doi=10.1128/CMR.00051-10|pmid=21482730|pmc=3122489}}</ref>

== Treatment ==
{{Main|Antimalarial medication}}

===History===
{{See also|History of malaria}}
In 1640, Huan del Vego first employed the [[tincture]] of the [[cinchona]] bark for treating malaria; the native Indians of [[Peru]] and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "[[Jesuits]]' bark" to [[England]]. Its first recorded use there was by John Metford of [[Northampton]] in 1656. [[Richard Morton (physician)|Morton]] (1696) presented the first detailed description of the clinical picture of malaria and of its treatment with cinchona. [[Gize]] (1816) studied the extraction of crystalline [[quinine]] from the cinchona bark and [[Pierre Joseph Pelletier|Pelletier]] and [[Joseph Bienaimé Caventou|Caventou]] (1820) in [[France]] extracted pure quinine [[alkaloid]]s, which they named quinine and [[cinchonine]].<ref>{{cite journal|last1=Greenwood|first1=David|title=The quinine connection|journal=Journal of Antimicrobial Chemotherapy|date=1992|volume=30|issue=4|pages=417–427|doi=10.1093/jac/30.4.417|pmid=1490916}}</ref><ref>{{cite journal|last1=Kaufman|first1=Teodoro S.|last2=Rúveda|first2=Edmundo A.|title=The Quest for Quinine: Those Who Won the Battles and Those Who Won the War|journal=Angewandte Chemie International Edition|date=28 January 2005|volume=44|issue=6|pages=854–885|doi=10.1002/anie.200400663|pmid=15669029}}</ref> The total synthesis of quinine was achieved by American chemists R.B. Woodward and W.E. Doering in 1944. Woodward received the Nobel Prize in Chemistry in 1965.<ref>{{cite journal|last1=Todd|first1=L.|last2=Cornforth|first2=J.|last3=T.|first3=A. R.|last4=C.|first4=J. W.|title=Robert Burns Woodward. 10 April 1917-8 July 1979|journal=Biographical Memoirs of Fellows of the Royal Society|date=1981|volume=27|pages=628–695|doi=10.1098/rsbm.1981.0025|doi-access=|s2cid=71742454 }}</ref>

Attempts to make synthetic antimalarials began in 1891. [[Quinacrine|Atabrine]], developed in 1933, was used widely throughout the Pacific in World War II, but was unpopular because of its adverse effects.<ref>{{cite journal|last1=Bispham|first1=W. N.|title=Toxic Reactions Following the Use of Atabrine in Malaria 1|journal=The American Journal of Tropical Medicine and Hygiene|date=1941|volume=s1-21|issue=3|pages=455–459|doi=10.4269/ajtmh.1941.s1-21.455}}</ref> In the late 1930s, the Germans developed [[chloroquine]], which went into use in the North African campaigns. Creating a secret military project called [[Project 523]], [[Mao Zedong]] encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. [[Tu Youyou]] discovered [[artemisinin]] in the 1970s from sweet wormwood (''[[Artemisia annua]]''). This drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment. Tu won the Nobel Prize in Physiology or Medicine in 2015.<ref>{{cite journal|last1=Su|first1=Xin-Zhuan|last2=Miller|first2=Louis H.|title=The discovery of artemisinin and the Nobel Prize in Physiology or Medicine|journal=Science China Life Sciences|date=2015|volume=58|issue=11|pages=1175–1179|doi=10.1007/s11427-015-4948-7|pmid=26481135|pmc=4966551}}</ref>

=== Uncomplicated malaria ===
According to WHO guidelines 2010,<ref name=who2010>[https://web.archive.org/web/20100310202149/http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html Guidelines for the treatment of malaria, second edition] Authors: WHO. Number of pages: 194. Publication date: 2010. Languages: English. {{ISBN|978-92-4-154792-5}}</ref> [[artemisinin-based combination therapies]] (ACTs) are the recommended [[first-line therapy|first-line]] [[antimalarial]] treatments for uncomplicated malaria caused by ''P. falciparum''. WHO recommends combinations such as [[artemether/lumefantrine]], [[artesunate/amodiaquine]], [[artesunate/mefloquine]], [[artesunate/sulfadoxine/pyrimethamine]], and [[dihydroartemisinin/piperaquine]].<ref name=who2010/>

The choice of ACT is based on the level of resistance to the constituents in the combination. Artemisinin and its derivatives are not appropriate for monotherapy. As a second-line antimalarial treatment, when initial treatment does not work, an alternative ACT known to be effective in the region is recommended, such as artesunate plus tetracycline or [[doxycycline]] or [[clindamycin]], and [[quinine]] plus tetracycline or doxycycline or clindamycin. Any of these combinations is to be given for 7 days. For pregnant women, the recommended first-line treatment during the [[first trimester]] is quinine plus clindamycin for 7 days.<ref name=who2010/> Artesunate plus clindamycin for 7 days is indicated if this treatment fails. For travellers returning to nonendemic countries, [[atovaquone]]/[[proguanil]], artemether/lumefantrineany and quinine plus doxycycline or clindamycin are recommended.<ref name=who2010/>

=== Severe malaria ===
For adults, [[intravenous]] (IV) or [[intramuscular]] (IM) artesunate is recommended.<ref name=who2010/> Quinine is an acceptable alternative if parenteral artesunate is not available.<ref name=who2010/>

For children, especially in the malaria-endemic areas of Africa, artesunate IV or IM, quinine (IV infusion or divided IM injection), and artemether IM are recommended.<ref name=who2010/>

Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient's ability to tolerate oral medication earlier.<ref name=who2010/> Thereafter, complete treatment is recommended including a complete course of ACT or quinine plus clindamycin or doxycycline.<ref name=who2010/>

=== Vaccination ===
{{Main|Malaria vaccine}}

[[RTS,S]] is the only candidate for the malaria vaccine to have gone through clinical trials.<ref>{{cite journal|last1=Matuschewski|first1=Kai|title=Vaccines against malaria-still a long way to go|journal=The FEBS Journal|date=2017|volume=284 |issue=16|pages=S0264–410X(16)30982–3|doi=10.1111/febs.14107|pmid=28500775|doi-access=free}}</ref> Analysis of the results of the phase III trial (conducted between 2011 and 2016) revealed a rather low efficacy (20-39% depending on age, with up to 50% in 5–17-month aged babies), indicating that the vaccine will not lead to full protection and eradication.<ref>{{cite journal|last1=Mahmoudi|first1=Shima|last2=Keshavarz|first2=Hossein|title=Efficacy of phase 3 trial of RTS, S/AS01 malaria vaccine: The need for an alternative development plan|journal=Human Vaccines & Immunotherapeutics|date=2017|volume=13|issue=9|pages=2098–2101|doi=10.1080/21645515.2017.1295906|pmid=28272979|pmc=5612527}}</ref>

On October 6, 2021, the World Health Organization recommended malaria vaccination for children at risk.<ref>{{Cite web|title=WHO recommends groundbreaking malaria vaccine for children at risk|url=https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-risk|access-date=2021-11-15|website=www.who.int|language=en}}</ref>

==Cancer==

The [[International Agency for Research on Cancer]] (IARC) has classified malaria due to ''P. falciparum'' as a Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans.<ref>{{cite journal|last1=De Flora|first1=S|last2=La Maestra|first2=S|title=Epidemiology of cancers of infectious origin and prevention strategies|journal=Journal of Preventive Medicine and Hygiene|date=2015|volume=56|issue=1|pages=E15–20|doi=10.15167/2421-4248/jpmh2015.56.1.470|pmid=26789827|pmc=4718340}}{{open access}}</ref> Its association with a blood cell ([[lymphocyte]]) cancer called [[Burkitt's lymphoma]] is established. Burkitt's lymphoma was discovered by [[Denis Parsons Burkitt|Denis Burkitt]] in 1958 by African children, and he later speculated that the cancer was likely due to certain infectious diseases. In 1964, a virus, later called [[Epstein–Barr virus]] (EBV) after the discoverers, was identified from the cancer cells. The virus was subsequently proved to be the direct cancer agent and is now classified as [[List of IARC Group 1 carcinogens|Group 1 carcinogen]].<ref>{{cite journal|last1=Bouvard|first1=Véronique|last2=Baan|first2=Robert|last3=Straif|first3=Kurt|last4=Grosse|first4=Yann|last5=Secretan|first5=Béatrice|last6=Ghissassi|first6=Fatiha El|last7=Benbrahim-Tallaa|first7=Lamia|last8=Guha|first8=Neela|last9=Freeman|first9=Crystal|last10=Galichet|first10=Laurent|last11=Cogliano|first11=Vincent|title=A review of human carcinogens—Part B: biological agents|journal=The Lancet Oncology|date=2009|volume=10|issue=4|pages=321–322|doi=10.1016/S1470-2045(09)70096-8|pmid=19350698|url=https://eprints.whiterose.ac.uk/182093/1/mono100B.pdf|display-authors=8}}</ref>

In 1989, it was realised that EBV requires other infections such as malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt's lymphoma decreased with effective treatment of malaria over several years.<ref>{{cite journal|last1=Geser|first1=A.|last2=Brubaker|first2=G.|last3=Draper|first3=C.C.|title=Effect of a malaria suppression program on the incidence of African Burkitt's lymphoma|journal=American Journal of Epidemiology|date=1989|volume=129|issue=4|pages=740–752|doi=10.1093/oxfordjournals.aje.a115189|pmid=2923122}}</ref> The actual role played by ''P. falciparum'' remained unclear for the next two-and-half decades. EBV had been known to induce lymphocytes to become cancerous using its viral proteins (antigens such as [[EBNA-1]], [[EBNA-2]], [[Epstein–Barr virus latent membrane protein 1|LMP1]], and [[Epstein–Barr virus latent membrane protein 2|LMP2A]]).<ref>{{cite journal|last1=Rajcani|first1=Julius|last2=Szenthe|first2=Kalman|last3=Banati|first3=Ferenc|last4=Szathmary|first4=Susan|title=Survey of Epstein Barr Virus (EBV) Immunogenic Proteins and their Epitopes: Implications for Vaccine Preparation|journal=Recent Patents on Anti-Infective Drug Discovery|date=2014|volume=9|issue=1|pages=62–76|doi=10.2174/1574891X09666140828114812|pmid=25164057}}</ref><ref>{{cite journal|last1=Wang|first1=Yuyan|last2=Banerjee|first2=Shuvomoy|last3=Ding|first3=Ling|last4=Cai|first4=Cankun|last5=Wei|first5=Fang|last6=Cai|first6=Qiliang|title=The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers|journal=Virologica Sinica|date=2017|volume=32|issue=5|pages=357–368|doi=10.1007/s12250-017-4081-9|pmid=29116588|pmc=6704201|doi-access=free}}</ref> From 2014, it became clear that ''P. falciparum'' contributes to the development of the lymphoma. ''P. falciparum''-infected erythrocytes directly bind to [[B lymphocytes]] through the CIDR1α domain of PfEMP1. This binding activates [[toll-like receptors]] ([[TLR7]] and [[TLR10]]) causing continuous activation of lymphocytes to undergo proliferation and differentiation into [[plasma cells]], thereby increasing the secretion of [[IgM]] and [[cytokines]].<ref>{{cite journal|last1=van Tong|first1=Hoang|last2=Brindley|first2=Paul J.|last3=Meyer|first3=Christian G.|last4=Velavan|first4=Thirumalaisamy P.|title=Parasite Infection, Carcinogenesis and Human Malignancy|journal=eBioMedicine|date=2017|volume=15|pages=12–23|doi=10.1016/j.ebiom.2016.11.034|pmid=27956028|pmc=5233816}}{{open access}}</ref>  This, in turn, activates an enzyme called [[activation-induced cytidine deaminase]] (AID), which tends to cause mutation in the DNA (by [[double-strand break]]) of EBV-infected lymphocytes. The damaged DNA undergoes uncontrolled [[DNA replication|replication]], thus making the cell cancerous.<ref>{{cite journal|last1=Thorley-Lawson|first1=David|last2=Deitsch|first2=Kirk W.|last3=Duca|first3=Karen A.|last4=Torgbor|first4=Charles|last5=Knoll|first5=Laura J|title=The Link between ''Plasmodium falciparum'' Malaria and Endemic Burkitt's Lymphoma—New Insight into a 50-Year-Old Enigma|journal=PLOS Pathogens|date=2016|volume=12|issue=1|pages=e1005331|doi=10.1371/journal.ppat.1005331|pmid=26794909|pmc=4721646 |doi-access=free }}{{open access}}</ref>

== Influence on the human genome ==
{{Further|Genetic resistance to malaria}}
The high [[death|mortality]] and [[morbidity]] caused by ''P.&nbsp;falciparum'' has placed great [[Selection (biology)|selective pressure]] on the [[human genome]]. Several genetic factors provide [[genetic resistance to malaria|some resistance to ''Plasmodium'' infection]], including [[sickle cell trait]], [[thalassaemia]] traits, [[glucose-6-phosphate dehydrogenase deficiency]], and the absence of [[Duffy antigen]]s on red blood cells.<ref name="Kwiatkowski 2005">{{Cite journal |author=Kwiatkowski DP |title=How malaria has affected the human genome and what human genetics can teach us about malaria |journal=American Journal of Human Genetics |volume=77 |issue=2 |pages=171–92 |year=2005 |pmid=16001361 |pmc=1224522 |doi=10.1086/432519}} {{open access}}</ref><ref name="Hedrick 2011">{{Cite journal |author=Hedrick PW |title=Population genetics of malaria resistance in humans |journal=Heredity |year=2011 |volume=107 |issue=4 |pages=283–304 |pmid=21427751 |doi=10.1038/hdy.2011.16 |pmc=3182497}} {{open access}}</ref> E. A. Beet, a doctor working in [[Southern Rhodesia]] (now [[Zimbabwe]]) had observed in 1948 that [[sickle-cell disease]] was related to a lower rate of malaria infections.<ref>{{cite journal|last1=Beet|first1=EA|title=Sickle cell disease in the Balovale District of Northern Rhodesia|journal=East African Medical Journal|date=1946|volume=23|pages=75–86|pmid=21027890}}</ref> This suggestion was reiterated by [[J. B. S. Haldane]] in 1948, who suggested that [[thalassaemia]] might provide similar protection.<ref>{{cite journal|last1=Hedrick|first1=P W|title=Population genetics of malaria resistance in humans|journal=Heredity|date=2011|volume=107|issue=4|pages=283–304|doi=10.1038/hdy.2011.16|pmid=21427751|pmc=3182497}}</ref> This hypothesis has since been confirmed and extended to [[hemoglobin E]]<ref>{{cite journal|last1=Chotivanich|first1=K|last2=Udomsangpetch|first2=R|last3=Pattanapanyasat|first3=K|last4=Chierakul|first4=W|last5=Simpson|first5=J|last6=Looareesuwan|first6=S|last7=White|first7=N|title=Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria.|journal=Blood|date=2002|volume=100|issue=4|pages=1172–6|pmid=12149194|doi=10.1182/blood.V100.4.1172.h81602001172_1172_1176|doi-access=free}}</ref> and [[hemoglobin C]].<ref>{{cite journal|last1=Verra|first1=Federica|last2=Simpore|first2=Jacques|last3=Warimwe|first3=George M.|last4=Tetteh|first4=Kevin K.|last5=Howard|first5=Tevis|last6=Osier|first6=Faith H. A.|last7=Bancone|first7=Germana|last8=Avellino|first8=Pamela|last9=Blot|first9=Isa|last10=Fegan|first10=Greg|last11=Bull|first11=Peter C.|last12=Williams|first12=Thomas N.|last13=Conway|first13=David J.|last14=Marsh|first14=Kevin|last15=Modiano|first15=David|last16=Hall|first16=Neil|title=Haemoglobin C and S Role in Acquired Immunity against ''Plasmodium falciparum'' Malaria|journal=PLOS ONE|date=3 October 2007|volume=2|issue=10|pages=e978|doi=10.1371/journal.pone.0000978|pmid=17912355|pmc=1991593|display-authors=8|bibcode=2007PLoSO...2..978V|doi-access=free}}</ref>

== See also ==
* [[Malaria Atlas Project]]
* [[List of parasites (human)]]
* [[UCSC Malaria Genome Browser]]

== References ==
{{Reflist|30em}}

==Further reading==
* [https://web.archive.org/web/20070623184554/http://www.agenciadenoticias.unal.edu.co/articulos/ciencia_tecnologia/ciencia_tecnologia_20070508_malaria.html Colombian scientists develop computational tool to detect ''Plasmodium falciparum'' (in Spanish)]
* {{cite journal |last=Allison |first=A.C. |title=Protection Afforded by Sickle-cell Trait Against Subtertian Malarial Infection |journal=Br Med J |volume=1 |issue=4857 |pages=290–4 |date=February 1954 |pmid=13115700 |pmc=2093356 |doi=10.1136/bmj.1.4857.290 }}
* {{cite journal |last=Allison |first=AC |title=Polymorphism and Natural Selection in Human Populations |journal=Cold Spring Harb. Symp. Quant. Biol. |volume=29 |pages=137–49 |year=1964 |pmid=14278460 | doi = 10.1101/sqb.1964.029.01.018 }}
* {{cite journal |last1=Cholera |first1=Rushina |last2=Brittain |first2=Nathaniel J. |last3=Gillrie |first3=Mark R. |last4=Lopera-Mesa |first4=Tatiana M. |last5=Diakité |first5=Séidina A. S. |last6=Arie |first6=Takayuki |last7=Krause |first7=Michael A. |last8=Guindo |first8=Aldiouma |last9=Tubman |first9=Abby |last10=Fujioka |first10=Hisashi |last11=Diallo |first11=Dapa A. |last12=Doumbo |first12=Ogobara K. |last13=Ho |first13=May |last14=Wellems |first14=Thomas E. |last15=Fairhurst |first15=Rick M. |title=Impaired cytoadherence of Plasmodium falciparum -infected erythrocytes containing sickle hemoglobin |journal=Proceedings of the National Academy of Sciences |date=22 January 2008 |volume=105 |issue=3 |pages=991–996 |doi=10.1073/pnas.0711401105 |pmid=18192399 |pmc=2242681 |bibcode=2008PNAS..105..991C |doi-access=free }}
* {{cite journal |last1=Mockenhaupt |first1=Frank P |last2=Ehrhardt |first2=Stephan |last3=Otchwemah |first3=Rowland |last4=Eggelte |first4=Teunis A |last5=Anemana |first5=Sylvester D |last6=Stark |first6=Klaus |last7=Bienzle |first7=Ulrich |last8=Kohne |first8=Elisabeth |title=Limited influence of haemoglobin variants on ''Plasmodium falciparum'' msp1 and msp2 alleles in symptomatic malaria |journal=Transactions of the Royal Society of Tropical Medicine and Hygiene |date=May 2004 |volume=98 |issue=5 |pages=302–310 |doi=10.1016/j.trstmh.2003.10.001 |pmid=15109555}}
* {{cite book |last2=Janovy |first2=John |last1=Roberts |first1=Larry S. |title=Foundations of Parasitology |publisher=McGraw-Hill Education (ISE Editions) |year=2005 |isbn=978-0-07-111271-0 |edition=7th}}

==External links==
{{Scholia|topic}}
* [https://www.cdc.gov/dpdx/malaria/ Malaria parasite species info at CDC]
* [http://atlas.or.kr/atlas/alphabet_view.php?my_codeName=Plasmodium%20falciparum Web Atlas of Medical Parasitology]
* [http://eol.org/pages/10408873/overview Species profile at Encyclopedia of Life]
* [https://www.uniprot.org/taxonomy/5833 Taxonomy at UniProt]
* [http://scientistsagainstmalaria.net/parasite/plasmodium-falciparum Profile at Scientists Against Malaria]
* [http://www.sanger.ac.uk/resources/downloads/protozoa/plasmodium-falciparum.html Genome info at Wellcome Trust Sanger Institute]
* [http://plasmodb.org/ PlasmoDB: The Plasmodium Genome Resource]
* [http://areslab.ucsc.edu/ UCSC Plasmodium Falciparum Browser]
* [http://www.vardb.org/vardb/pathogens/plasmodium.falciparum.html Gene info at  Kyoto University]

{{Malaria}}
{{Chromalveolate diseases}}
{{Taxonbar|from=Q311383}}
{{Authority control}}

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