Editing Plasmodium falciparum (section)

== 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.