Plasmodium falciparum 544177 225921653 2008-07-16T00:57:04Z Rjwilmsi 203434 gen fixes + link/fix date fields in cite templates (explanation [[User:Rjwilmsi#My_correction_of_citation_templates|here]]) using [[Project:AutoWikiBrowser|AWB]] {{Taxobox | color = khaki | name = ''Plasmodium falciparum'' | image = Plasmodium_falciparum_01.png | image_width = 240px | image_caption = Blood smear of ''Plasmodium falciparum'' | regnum = [[Protista]] | phylum = [[Apicomplexa]] | classis = [[Aconoidasida]] | ordo = [[Haemosporida]] | familia = [[Plasmodiidae]] | genus = ''[[Plasmodium]]'' | species = '''''P. falciparum''''' | binomial = ''Plasmodium falciparum'' | binomial_authority = [[William Henry Welch|Welch]], [[1897]] }} '''''Plasmodium falciparum''''' is a [[protozoa]]n [[parasite]], one of the species of ''[[Plasmodium]]'' that cause [[malaria]] in humans. It is transmitted by ''[[Anopheles]]'' [[mosquito]]es. ''P. falciparum'' is the most dangerous of these infections as ''P. falciparum'' malaria has the highest rates of complications and mortality. In addition it accounts for 80% of all human malarial infections and 90% of the deaths. It is more prevalent in sub-Saharan Africa than in other regions of the world. == Background == Malaria is caused by an infection with protozoa of the genus ''Plasmodium.'' The name malaria comes from the Italian ''mala aria,'' meaning bad air, comes from the linkage suggested by [[Giovanni Maria Lancisi]] ([[1717]]) of [[malaria]] with the poisonous vapours of swamps. The organism itself was first seen by [[Charles Louis Alphonse Laveran|Laveran]] on November 6th [[1880]] at a military hospital in [[Constantine, Algeria]], when he discovered a microgametocyte exflagellating. [[Manson]] (1894) hypothesised that mosquitoes could transmit malaria - an association made considerably earlier in [[India]], possibly as early as 2000BC{{Fact|date=February 2007}}. This hypothesis was experimentally confirmed independently by [[Giovanni Battista Grassi]] and [[Ronald Ross]] in [[1898]]. Grassi ([[1900]]) proposed an exerythrocytic stage in the life cycle and this was later confirmed by Short, Garnham, Covell and Shute ([[1948]]) who found ''[[Plasmodium vivax]]'' in the human liver. It is globally the most important [[parasitic disease]] of man and claims the lives of more children worldwide than any other infectious disease. Since [[1900]] the area of the world exposed to malaria has been halved but in this time two billion more are presently exposed. Morbidity as well as mortality is substantial. Infection rates in children in endemic areas are of the order of 50%: chronic infection has been shown to reduce school scores by up to 15%. Reduction in the incidence of malaria coincides with increased economic output. While there are no effective vaccines for any of the six or more species that cause human malaria, drugs have been employed for centuries. 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 Dr John Metford of [[Northampton]] in 1656. [[Morton]]{{dn}} ([[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]]. == Plasmodium Life Cycle == {{seealso|Plasmodium falciparum biology}} When an infected mosquito bites a human, '''sporozoites''' enter the human circulation. These go to and penetrate the liver cells, where they asexually reproduce, via the process of '''schizogony'''. This intracellular, asexually dividing form of the parasite is known as a '''schizont''', and because this schizont is in liver cells and not RBCs, it is known as the ''exoerythrocytic'' schizont stage. (In Plasmodium vivax and Plasmodium ovale species, the development of the schizont is retarded, and a "resting" stage of the parasite, called the Hypnozoite, is formed; however, this is not the case in Plasmodium falciparum.) When the hepatocytes burst, exoerythrocytic schizonts release '''merozoites''' into the blood, which are capable of infecting erythrocytes. Inside the erythrocytes, the merozoites develop into ring-like '''trophozoites''', which then form the ''erythrocytic'' schizonts. Mature erythrocytic schizonts form merozoites again by breaking apart inside the erythrocytes. These merozoites are a ''transient intracellular'' form, either rapidly infecting new red blood cells to complete the erythrocytic cycle, or dying. In addition, when infection of new blood cells occurs, instead of forming trophozoites the parasites may grow into the '''immature gametocytes'''. These can be taken up in the blood meal of another feeding mosquito. The male gametocyte undergoes rapid nuclear division and produces a '''flagellated microgamete''', which fertilizes the female gametocyte forming a zygote. The zygote develops into an '''ookinete''', which then sticks to the gut wall of the mosquito, moves to the outermost layer of the stomach to form an '''oocyst'''. When it breaks, it releases '''sporozoites''', which migrate to the salivary glands of the mosquito to restart the parasite's life cycle. == Treatment and drug resistance == Attempts to make synthetic antimalarials began in 1891. [[Quinacrine|Atabrine]] was developed in 1928, was used widely throughout the Pacific in World War II but was deeply unpopular because of the yellowing of the skin it caused. In the late 1930s, the Germans developed [[chloroquine]], which went into use in the North African campaigns. [[Mao Zedong]] encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. [[Artemisinin]] was discovered in the 1970s based on a medicine described in China in the year 340. This new drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment. In 1976 ''P. falciparum'' was successfully [[Malaria culture|cultured]] ''in vitro'' for the first time which facilitated the development of new drugs substantially.<ref name="Trager1976">{{Cite journal | issn = 00368075 | volume = 193 | issue = 4254 | pages = 673–5 | last = Trager | first = W | coauthors = J B Jensen | title = Human malaria parasites in continuous culture | journal = Science (New York, N.Y.) | date = 1976-08-20 | pmid=781840 | doi = 10.1126/science.781840 }}</ref> == Vaccination == Although an antimalarial vaccine is urgently needed, infected individuals never develop a sterilizing (complete) immunity, making the prospects for such a vaccine dim. The parasites live inside cells, where they are largely hidden from the immune response. Infection has a profound effect on the [[immune system]] including immune suppression. [[Dendritic cell]]s suffer a maturation defect following interaction with infected [[erythrocytes]] and become unable to induce protective liver-stage [[immunity (medical)|immunity]]. Infected erythrocytes directly adhere to and activate peripheral blood [[B cells]] from nonimmune donors. The ''var'' gene products, a group of highly expressed surface [[antigen]]s, bind the Fab and Fc fragments of human [[immunoglobulin]]s in a fashion similar to protein A to ''[[Staphylococcus aureus]]'' and this may offer some protection to the parasite from the human immune system. Despite the poor prospects for a fully protective vaccine, it may be possible to develop a vaccine that would reduce the severity of malaria for children living in endemic areas. == Microscopic appearance == [[Image:Plasmodium falciparum 02.jpg|thumb|280px|Blood smear from a ''P. falciparum'' [[Malaria culture|culture]] (K1 strain). Several red blood cells have ring stages inside them. Close to the center there is a schizont and on the left a trophozoite.]] Among medical professionals, the preferred method to diagnose malaria and determine which species of ''Plasmodium'' is causing the infection is by examination of a [[blood film]] microscopically in a laboratory. Each species has distinctive physical characteristics that are apparent under a [[microscope]]. In ''P. falciparum'', only early [[trophozoite]]s and [[gametocyte]]s are seen in the peripheral blood. It is unusual to see mature trophozoites or [[wiktionary:schizont|schizonts]] in peripheral blood smears as these are usually sequestered in the tissues. The parasitised erythrocytes are not enlarged and it is common to see cells with more than one parasite within them (multiply parasitised erythrocytes). Occasionally, faint comma-shaped red dots are seen on the red cell surface called "Maurer's dots". The comma shaped dots can also appear as pear shaped blotches. == Plasmodium and the human genome == In the 50,000 years since ''Plasmodium'' first infected humans {{Fact|date=June 2008}}, the presence of the parasite in human populations has altered the human genome in a multitude of ways, as humans have been forced to develop resistance to the disease. Beet, a doctor working in [[Southern Rhodesia]] (now [[Zimbabwe]]) in [[1948]], first suggested that [[sickle-cell disease]] could offer some protection to malaria. This suggestion was reiterated by [[J. B. S. Haldane]] in [[1949]] who suggested that thalassaemia could provide similar protection. This hypothesis has since been confirmed and has been extended to [[hemoglobin C]] and [[hemoglobin E]], abnormalities in [[ankyrin]] and [[spectrin]] ([[ovalocytosis]] , [[elliptocytosis]]), in [[glucose-6-phosphate dehydrogenase deficiency]] and [[pyruvate kinase deficiency]], loss of the Gerbich antigen ([[glycophorin C]]) and the [[Duffy antigen]] on the [[erythrocytes]], [[thalassemia]]s and variations in the [[major histocompatibility complex]] classes 1 and 2 and [[CD32]] and [[CD36]]. In 1995 a consortium - the malaria [[genome]] project (MGP) - was set up to sequence the genome of ''P. falciparum''. The genome of the parasite [[mitochondrion]] was reported in 1995, that of the [[plastid]] (apicoplast) in 1996, 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 on 3rd October 2002. The ~24 megabase genome is extremely AT rich (~80%) and is organised into 14 chromosomes: just over 5300 genes were described. == Evolution of ''Plasmodium falciparum'' == The closest relative of ''Plasmodium falciparum'' is ''[[Plasmodium reichenowi]]'', a parasite of [[chimpanzee]]s. Molecular clock analyses suggest that ''P. falciparum'' is as old as the human line; the two species diverged at the same time as humans and chimpanzees<ref name="Escalante et al. 1995">{{Cite journal | issn = 07374038 | volume = 12 | issue = 4 | pages = 616–26 | last = Escalante | first = AA | coauthors = E Barrio, FJ Ayala | title = Evolutionary origin of human and primate malarias: evidence from the circumsporozoite protein gene | journal = Molecular Biology and Evolution | date = 1995 | pmid=7659017 }}</ref>. However, low levels of polymorphism within the ''P. falciparum'' genome suggest a much more recent origin<ref name="Hartl 2004">{{Cite journal | issn = 17401526 | 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 = 2004-01 | pmid=15035005 | doi = 10.1038/nrmicro795 }}</ref>. It may be that this discrepancy exists because ''P. falciparum'' is old, but its population recently underwent a great expansion<ref name="Joy et al. 2003">{{Cite journal | issn = 01934511 | volume = 300 | issue = 5617 | pages = 318–21 | last = Joy | first = DA | coauthors = Feng X, Mu J, Furuya T, Chotivanich K, Krettli AU, Ho M, Wang A, White NJ, Suh E, Beerli P, Su XZ. | title = Early origin and recent expansion of Plasmodium falciparum | journal = Science | date = 2003-04-11 | pmid=15035005 | doi = 10.1038/nrmicro795 }}</ref>. ''P. falciparum'' and ''P. reichenowi'' are not closely related to the other ''Plasmodium'' species that parasitize humans, or indeed mammals generally. It has been argued that these two species originated from a parasite of birds<ref name="Rathore et al. 2001">{{Cite journal | issn = 01666851 | volume = 114 | issue = 1 | pages = 89–94 | last = Rathore | first = D | coauthors = Wahl AM, Sullivan M, McCutchan TF | title = A phylogenetic comparison of gene trees constructed from plastid, mitochondrial and genomic DNA of Plasmodium species | journal = Molecular and Biochemical Parasitology | date = 2001-04-25 | pmid=11356517 | doi = 10.1016/S0166-6851(01)00241-9 }}</ref>. More recent analyses do not support this, however, instead suggesting that the ability to parasitize mammals evolved only once within the genus ''Plasmodium''<ref name="Yotoko and Elisei 2006">{{Cite journal | issn = 09475745 | volume = 44 | issue = 4 | pages = 265–73 | last = Yotoko | first = KSC | coauthors = C Elisei | title = Malaria parasites (Apicomplexa, Haematozoea) and their relationships with their hosts: is there an evolutionary cost for the specialization? | journal = Journal of Zoological Systematics and Evolutionary Research | date = 2006-11 | doi = 10.1111/j.1439-0469.2006.00377.x }}</ref>. More recently, ''P. falciparum'' has evolved in response to human interventions. Most strains of malaria can be treated with chloroquine, but ''P. falciparum'' has developed resistance to this treatment. A combination of quinine and tetracycline has also been used, but there are strains of ''P. falciparum'' that have grown resistant to this treatment as well. Different strains of ''P. falciparum'' have grown resistant to different treatments. Often the resistance of the strain depends on where it was contracted. Many cases of malaria that come from parts of the Caribbean and west of the Panama Canal as well as the Middle East and Egypt can often be treated with chloroquine, since they have not yet developed resistance. Nearly all cases contracted in Africa, India, and southeast Asia have grown resistant to this medication and there have been cases in Thailand and Cambodia in which the strain has been resistant to nearly all treatments. Often the strain grows resistant to the treatment in areas where the use is not as tightly regulated. Like most [[Apicomplexa]], malaria parasites harbor a plastid similar to plant [[chloroplast]]s, which they probably acquired by engulfing (or being invaded by) a [[eukaryotic]] alga, and retaining the algal plastid as a distinctive [[organelle]] encased within four membranes (see [[endosymbiotic theory]]). The [[apicomplexa]]n plastid, or [[apicoplast]], is an essential organelle, thought to be involved in the synthesis of lipids and several other compounds, and provides an attractive target for antimalarial drug development, particularly in light of the emergence of parasites resistant to chloroquine and other existing antimalarial agents. == Plasmodium falciparum and Sickle Cell Anemia == Individuals with sickle cell anemia and individuals with sickle cell trait do have reduced parasitemia when compared to wild typed individuals for the hemoglobin protein in red blood cells. Studies have shown these genetic deviations of hemoglobin from normal states provide protection against the deadly parasite that causes malaria (Allison, 1954). Of the four malarial parasites, Plasmodium falciparum causes the most fatal and medically severe form. Malaria is prevalent in tropical countries with an incidence of 300 million per year and a mortality rate of 1to 2 million per year. Roughly 50% of all malarial infections are caused by Plasmodium falciparum (Roberts and Janovy Jr., 2005) Upon infection via a bite from an infected Anopheles mosquito, sporozoites devastate the human body by first, infecting the liver. While in the liver, sporozoites undergo asexual development and trophozoites are released into the blood stream. The trophozoites further develop and reproduce by invading red blood cells. During the reproduction cycle, Plasmodium falciparum produces up to 40,000 merozoites in one day. Other blood sporozoans, such as Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae, that infect humans and cause malaria do not have such a productive cycle for invasion. The process of bursting red blood cells does not have any symptoms, however destruction of the cells does cause anemia since the bone marrow cannot compensate for the damage. When red blood cells rupture, hemozoin wastes cause cytokine release, chills, and then fever (Roberts and Janovy Jr., 2005). The Plasmodium falciparum trophozoites develop sticky knobs in red blood cell that adheres to endothelial cells in blood vessels, thus evading clearance in the spleen. The acquired adhesive nature of the red blood cells may cause cerebral malaria when sequestered cells prevent oxygenation of the brain. Symptoms of cerebral malaria include impaired consciousness, convulsions, neurological disorder, and coma (Brown University). Additional complications from Plasmodium falciparum induced malaria include advanced immunosupression (Roberts and Janovy Jr., 2005). Individuals with sickle cell trait and sickle cell anemia are privileged because they have altered sticky knobs. Research by Cholera, R., Brittain, N., Gillrie, M. et al. (2007) has shown that show that parasitemia (the ability of a parasite to infect) because merozoites of each parasite species that cause malaria invade the red blood cell in three stages: contact, attachment, and endocytosis. Individuals suffering from sickle cell anemia have deformed red blood cells that interfere with the attachment phase and Plasmodium falciparum and the other forms of malaria have trouble with endocytosis. These individuals have reduced attachment when compared to red blood cells with the normally functioning hemoglobin because of differing protein interactions. Normally, merozoites enter red blood cells through two PfEMP-1 protein dependent interactions. These interactions promote the malaria inflammatory response associated with symptoms of chills and fever. When these proteins are impaired as in sickle cell cases, parasites cannot undergo cytoadherance interactions and cannot infect the cells, therefore sickle cell anemic individuals and individuals carrying the sickle cell trait have lower parasite loads and shorter time for symptoms than individuals expressing normal red blood cells (Mockenhaupt, 2004). Individuals with sickle cell anemia may also experience greatly reduced symptoms of malaria because Plasmodium falciparum trophozoites cannot bind to hemoglobin in order to form sticky knobs. Without knob binding complexes, which is an exclusive feature of Plasmodium falciparum, red blood cells do not stick to endothelial walls of blood vessels and infected individuals do not experience symptoms such as cerebral malaria (Cholera, R., Brittain, N., Gillrie, M. et al. 2007). Many may wonder why natural selection has not phased out sickle cell anemia. The answer to that question lies within answers generated by Cholera, R., Brittain, N., Gillrie, M. et al. (2007). Individuals with sickle cell trait are greatly desired in areas where malarial infections are endemic. Malaria kills between 1 and 2 million people per year. It is the leading cause of death amongst children in tropical regions. Individuals with sickle cell deformities are able to fight Plasmodium parasite infections and do not become victims of malarial demise. Therefore, individuals expressing the genes and individuals carrying genes are selected to remain within the population (Allison 1964). To no surprise the incidence of sickle cell anemia match endemic regions for malarial infections. == References == {{reflist}} == Sources and further reading == === Overview === * [http://www.tulane.edu/~wiser/protozoology/notes/malaria.html Introductory] * [http://www.ratsteachmicro.com/Malaria_notes/HCOE_CAI_Review_Notes_Malaria.htm Overview] * [http://www.tulane.edu/~wiser/malaria/cmb.html Malaria biology] * [http://www.roche.nl/ziektebeeld/malaria/malaria2.gif Life cycle cartoon] === Spatial distribution === * [http://www.map.ox.ac.uk Malaria Atlas Project] === Blood slides === * [http://home.austarnet.com.au/wormman/paraimg/pfalcipt.jpg Blood forms] * [http://home.austarnet.com.au/wormman/paraimg/pfalcipm.jpg Blood forms] * [http://www.yamagiku.co.jp/pathology/photo/photo206-7.htm Blood forms] * [http://www.yamagiku.co.jp/pathology/photo/photo206-8.htm Blood forms] * [http://www.yamagiku.co.jp/pathology/photo/photo206-1.htm Multiple blood forms] * [http://home.austarnet.com.au/wormman/paraimg/pfalcipg.jpg Female gametocyte] * [http://medschool.sums.ac.ir/users/parasito/Blood%20and%20tissue%20protozoa/Plasmodium%20%20falciparum%20gametocyte2.JPG Female gametocyte] * [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=&dopt=Abstract ncbi.nlm.nih.gov] === Case histories === * [http://www.med-chem.com/Para/Prob%20of%20Month/Prob%20of%20Month%2038%20February%2004.htm Case 1] * [http://www.med-chem.com/Para/Prob%20of%20Month/Prob%20of%20Month%2031%20July%2003.htm Case 2] * [http://www.yamagiku.co.jp/pathology/case/case206.htm Case 3] * [http://www.yamagiku.co.jp/pathology/case/case129.htm Case 4] === Pathology due to ''Plasmodium falciparum'' === ; Brain * [http://www.vh.org/adult/provider/pathology/CNSInfDisR2/Text/165.html Gross pathology] * [http://www.neuroanatomy.hpg.ig.com.br/Histopathology%20of%20malaria%20of%20brain.%20Mature%20schizontsss_2.jpg Low power H & E stain] * [http://www.neuroanatomy.hpg.ig.com.br/Histopathology%20of%20malaria%20of%20brain.%20Mature%20schizonts._2.jpg High power H & E stain showing parasite adherence to the vessel walls] ; Spleen * [http://www.yamagiku.co.jp/pathology/photo/photo206-2.htm Gross pathology] * [http://oac.med.jhmi.edu/Pathology/Idmicro/Parasite/037A_Full.html Low power H & E] * [http://www.yamagiku.co.jp/pathology/photo/photo206-3.htm Smear preparation] * [http://www.yamagiku.co.jp/pathology/photo/photo206-4.htm Smear preparation] ; Liver * [http://www.yamagiku.co.jp/pathology/photo/photo206-5.htm Low power H & E] * [http://medschool.sums.ac.ir/users/parasito/Blood%20and%20tissue%20protozoa/Malaria-schizont%20in%20liver500X.JPG High power H & E] ; Kidney * [http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/07MN_medulla_L.gif Low power H & E] * [http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/01MN_Ex_L.gif High power H & E] * [http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/05MN_Ex_HE3_L.gif High power H & E] * [http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/02MN_Ex_PAM1_L.gif Membrane stain] * [http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/06MN_Ex_PAM3_L.gif Membrane stain] === ''Plasmodium falciparum'' genome data === * {{cite journal | author = Gardner, M.J. | coauthors = Hall, N.; Fung, E.; White, O.; Berriman, M.; Hyman, R.W.; Carlton, J.M.; Pain, A.; Nelson, K.E.; Bowman, S.; Others, | year = 2002 | title = Genome sequence of the human malaria parasite Plasmodium falciparum | journal = Nature | volume = 419 | pages = 498–511 | doi = 10.1038/nature01097 }} * [http://plasmodb.org/ PlasmoDB: The Plasmodium Genome Resource] * [http://www.genedb.org/genedb/malaria GeneDB Plasmodium falciparum] * [http://www.wehi.edu.au/MalDB-www/who.html Genome] * [http://areslab.ucsc.edu/ UCSC Plasmodium Falciparum Browser] === Other === * [http://www.agenciadenoticias.unal.edu.co/articulos/ciencia_tecnologia/ciencia_tecnologia_20070508_malaria.html Colombian scientists develop computacional tool to detect the plasmodium falciparum (in spanish)] * Allison AC (1954) Protection afforded by sickle-cell trait against subtertian malareal infection. Br Med J 4857:290 –294. * Allison AC (1964) Polymorphism and Natural Selection in Human Populations Cold Spring Harb Symp Quant Biol 29:137–149. * Cholera, R, Brittain, N, Gillrie, M, Lopera-Mesa, T, Diakite, S, & Arie, T (2007). Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. * Mockenhaupt FP, et al. (2004) Limited influence of haemoglobin variants on Plasmodium falciparum msp1 and msp2 alleles in symptomatic malaria. Trans R Soc Trop Med Hyg 98:302–310. * Roberts, L, & Jonovy, Jr., J (2005). Foundations of Parasitology. New York: McGraw-Hill. [[Category:Apicomplexa]] [[Category:Malaria]] [[Category:Parasites]] [[ca:Plasmodi falcípar]] [[da:Plasmodium falciparum]] [[de:Malaria#Plasmodium_falciparum]] [[es:Plasmodium falciparum]] [[fr:Plasmodium falciparum]] [[hr:Plasmodium falciparum]] [[nl:Plasmodium falciparum]] [[ps:پلازموډيم فالسيپارم]] [[pl:Zarodziec sierpowy]] [[tr:Plasmodium falciparum]]