Editing Plasmodium falciparum (section)

===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>