| Plasmodium | |
|---|---|
 | |
| False-coloredelectron micrograph of asporozoite | |
Scientific classification | |
| Domain: | Eukaryota |
| Clade: | Sar |
| Clade: | Alveolata |
| Phylum: | Apicomplexa |
| Class: | Aconoidasida |
| Order: | Haemospororida |
| Family: | Plasmodiidae |
| Genus: | Plasmodium Marchiafava &Celli, 1885 |
Plasmodium is agenus of unicellulareukaryotes that areobligate parasites ofvertebrates andinsects. The life cycles ofPlasmodium species involve development in ablood-feeding insecthost which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue (often the liver) before entering the bloodstream to infectred blood cells. The ensuing destruction of host red blood cells can result inmalaria. During this infection, some parasites are picked up by a blood-feeding insect (mosquitoes in majority cases), continuing the life cycle.[1]
Plasmodium is a member of the phylumApicomplexa, a large group of parasitic eukaryotes. Within Apicomplexa,Plasmodium is in the orderHaemosporida and familyPlasmodiidae. Over 200 species ofPlasmodium have been described, many of which have been subdivided into 14 subgenera based on parasite morphology and host range. Evolutionary relationships among differentPlasmodium species do not always follow taxonomic boundaries; some species that are morphologically similar or infect the same host turn out to be distantly related.
Species ofPlasmodium are distributed globally wherever suitable hosts are found. Insect hosts are most frequentlymosquitoes of the generaCulex andAnopheles. Vertebrate hosts include reptiles, birds, and mammals.Plasmodium parasites were first identified in the late 19th century byCharles Laveran. Over the course of the 20th century, many other species were discovered in various hosts and classified, including five species that regularly infect humans:P. vivax,P. falciparum,P. malariae,P. ovale, andP. knowlesi.P. falciparum is by far the most lethal in humans, resulting in hundreds of thousands of deaths per year. A number ofdrugs have been developed to treatPlasmodium infection; however, the parasites have evolved resistance to each drug developed.
Although the parasite can also infect people viablood transfusion, this is very rare, andPlasmodium cannot be spread from person to person. Some of subspecies ofPlasmodium areobligate intracellular parasites.
The genusPlasmodium consists of alleukaryotes in the phylum Apicomplexa that both undergo the asexual replication process ofmerogony inside hostred blood cells and produce the crystalline pigmenthemozoin as a byproduct of digesting hosthemoglobin.[2]Plasmodium species contain many features that are common to other eukaryotes, and some that are unique to their phylum or genus. ThePlasmodiumgenome is separated into 14chromosomes contained in thenucleus.Plasmodium parasites maintaina single copy of their genome through much of the life cycle,doubling the genome only for a brief sexual exchange within themidgut of the insect host.[3] Attached to the nucleus is theendoplasmic reticulum (ER), which functions similarly to the ER in other eukaryotes. Proteins are trafficked from the ER to theGolgi apparatus which generally consists of a single membrane-bound compartment in Apicomplexans.[4] From here, proteins are trafficked to various cellular compartments or to the cell surface.[4]
Like other apicomplexans,Plasmodium species have several cellular structures at theapical end of the parasite that serve as specialized organelles for secreting effectors into the host. The most prominent are the bulbousrhoptries which contain parasite proteins involved in invading the host cell and modifying the host once inside.[5] Adjacent to the rhoptries are smaller structures termedmicronemes that contain parasite proteins required for motility as well as recognizing and attaching to host cells.[6] Spread throughout the parasite are secretoryvesicles calleddense granules that contain parasite proteins involved in modifying the membrane that separates the parasite from the host, termed theparasitophorous vacuole.[6]
Species ofPlasmodium also contain two large membrane-bound organelles ofendosymbiotic origin, themitochondrion and theapicoplast, both of which play key roles in the parasite'smetabolism. Unlike mammalian cells which contain many mitochondria,Plasmodium cells contain a single large mitochondrion that coordinates its division with that of thePlasmodium cell.[7] Like in other eukaryotes, thePlasmodium mitochondrion is capable of generating energy in the form ofATP via thecitric acid cycle; however, this function is only required for parasite survival in the insect host, and is not needed for growth in red blood cells.[7] A second organelle, the apicoplast, is derived from asecondary endosymbiosis event, in this case the acquisition of ared alga by thePlasmodium ancestor.[8] The apicoplast is involved in the synthesis of various metabolic precursors, includingfatty acids,isoprenoids,iron-sulphur clusters, and components of theheme biosynthesis pathway.[9]
The life cycle ofPlasmodium involves several distinct stages in the insect and vertebratehosts. Parasites are generally introduced into a vertebrate host by the bite of an insect host (generally a mosquito, with the exception of somePlasmodium species of reptiles).[10] Parasites first infect the liver or other tissue, where they undergo a single large round of replication before exiting the host cell to infecterythrocytes.[11] At this point, some species ofPlasmodium of primates can form a long-lived dormant stage called a hypnozoite,[12] which can remain in the liver for more than a year.[13] However, for mostPlasmodium species, the parasites in infected liver cells are only what are called merozoites. After emerging from the liver, they enter red blood cells, as explained above. They then go through continuous cycles of erythrocyte infection, while a small percentage of parasites differentiate into a sexual stage called a gametocyte which is picked up by an insect host taking a blood meal. In some hosts, invasion of erythrocytes byPlasmodium species can result in disease, called malaria. This can sometimes be severe, rapidly followed by death of the host (e.g.P. falciparum in humans). In other hosts,Plasmodium infection can apparently be asymptomatic.[10]
Even when humans have such subclinical plasmodial infections, there can nevertheless be very large numbers of multiplying parasites concealed in, particularly, the spleen and bone marrow. Certainly, this applies in the case ofP. vivax. These hidden parasites (in addition to hypnozoites) are thought to be the origin of instances of recurrentP. vivax malaria.[14]
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Within the red blood cells, the merozoites grow first to a ring-shaped form and then to a larger form called atrophozoite. Trophozoites then mature toschizonts which divide several times to produce new merozoites. The infected red blood cell eventually bursts, allowing the new merozoites to travel within the bloodstream to infect new red blood cells. Most merozoites continue this replicative cycle, however some merozoites upon infecting red blood cells differentiate into male or female sexual forms called gametocytes. These gametocytes circulate in the blood until they are taken up when a mosquito feeds on the infected vertebrate host, taking up blood which includes the gametocytes.[11]
In the mosquito, the gametocytes move along with theblood meal to the mosquito's midgut. Here thegametocytes develop into male and femalegametes whichfertilize each other, forming azygote. Zygotes then develop into a motile form called anookinete, which penetrates the wall of the midgut. Upon traversing the midgut wall, the ookinete embeds into the gut's exterior membrane and develops into an oocyst. Oocysts divide many times to produce large numbers of small elongatedsporozoites. These sporozoites migrate to the salivary glands of the mosquito where they can be injected into the blood of the next host the mosquito bites, repeating the cycle.[11]
Plasmodium belongs to thephylumApicomplexa, a taxonomic group of single-celled parasites with characteristicsecretory organelles at one end of the cell.[15] Within Apicomplexa,Plasmodium is within theorderHaemosporida, a group that includes all apicomplexans that live within blood cells.[16] Based on the presence of the pigmenthemozoin and the method ofasexual reproduction, the order is further split into four families, of whichPlasmodium is in thefamilyPlasmodiidae.[17]
The genusPlasmodium consists of over 200 species, generally described on the basis of their appearance in blood smears of infected vertebrates.[18] These species have been categorized on the basis of their morphology and host range into 14 subgenera:[17]
Species infectingmonkeys andapes with the exceptions ofP. falciparum andP. reichenowi (which together make up the subgenusLaverania) are classified in the subgenusPlasmodium. Parasites infecting othermammals including some primates (lemurs and others) are classified in the subgenusVinckeia. The five subgeneraBennettinia,Giovannolaia,Haemamoeba,Huffia, andNovyella contain the known avian malarial species.[19] The remaining subgenera:Asiamoeba,Carinamoeba,Lacertamoeba,Ophidiella,Paraplasmodium, andSauramoeba contain the diverse groups of parasites found to infect reptiles.[20]
More recent studies ofPlasmodium species using molecular methods have implied that the group's evolution has not perfectly followed taxonomy.[2] ManyPlasmodium species that are morphologically similar or infect the same hosts turn out to be only distantly related.[21] In the 1990s, several studies sought to evaluate evolutionary relationships ofPlasmodium species by comparingribosomal RNA and a surface protein gene from various species, finding the human parasiteP. falciparum to be more closely related to avian parasites than to other parasites of primates.[17] However, later studies sampling morePlasmodium species found the parasites of mammals to form a clade along with the genusHepatocystis, while the parasites of birds or lizards appear to form a separate clade with evolutionary relationships not following the subgenera:[17][22]
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Estimates for when differentPlasmodium lineages diverged have differed broadly. Estimates for the diversification of the order Haemosporida range from around 16.2 million to 100 million years ago.[17] There has been particular interest in dating the divergence of the human parasiteP. falciparum from otherPlasmodium lineages due to its medical importance. For this, estimated dates range from 110,000 to 2.5 million years ago.[17]
Plasmodium species are distributed globally. AllPlasmodium species are parasitic and must pass between a vertebrate host and an insect host to complete their life cycles. Different species ofPlasmodium display different host ranges, with some species restricted to a single vertebrate and insect host, while other species can infect several species of vertebrates and/or insects.
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Plasmodium parasites have been described in a broad array of vertebrate hosts including reptiles, birds, and mammals.[24] While many species can infect more than one vertebrate host, they are generally specific to one of theseclasses (such as birds).[24]
Humans are primarily infected byfive species ofPlasmodium, with the overwhelming majority of severe disease and death caused byPlasmodium falciparum.[25] Some species that infect humans can also infect other primates, and zoonoses of certain species (e.g.P. knowlesi) from other primates to humans are common.[25] Non-human primates also contain avariety ofPlasmodium species that do not generally infect humans. Some of these can cause severe disease in primates, while others can remain in the host for prolonged periods without causing disease.[26] Many other mammals also carryPlasmodium species, such as a variety ofrodents,ungulates, andbats. Again, some species ofPlasmodium can cause severe disease in some of these hosts, while many appear not to.[27]
Over 150 species ofPlasmodium infect a broad variety of birds. In general each species ofPlasmodium infects one to a few species of birds.[28]Plasmodium parasites that infect birds tend to persist in a given host for years or for the life time of the host, although in some casesPlasmodium infections can result in severe illness and rapid death.[29][30] Unlike withPlasmodium species infecting mammals, those infecting birds are distributed across the globe.[28]
Species from several subgenera ofPlasmodium infect diversereptiles.Plasmodium parasites have been described in most lizardfamilies and, like avian parasites, are spread worldwide.[31] Again, parasites can result either in severe disease or be apparently asymptomatic depending on the parasite and the host.[31]
A number ofdrugs have been developed over the years to controlPlasmodium infection in vertebrate hosts, particularly in humans.Quinine was used as a frontline antimalarial from the 17th century until widespreadresistance emerged in the early 20th century.[32] Resistance to quinine spurred the development of a broad array of antimalarial medications through the 20th century includingchloroquine,proguanil,atovaquone,sulfadoxine/pyrimethamine,mefloquine, andartemisinin.[32] In all cases, parasites resistant to a given drug have emerged within a few decades of the drugs deployment.[32] To combat this, antimalarial drugs are frequently used in combination, withartemisinin combination therapies currently the gold standard for treatment.[33] In general, antimalarial drugs target the life stages ofPlasmodium parasites that reside within vertebrate red blood cells, as these are the stages that tend to cause disease.[34] However, drugs targeting other stages of the parasite life cycle are under development in order to prevent infection in travelers and to prevent transmission of sexual stages to insect hosts.[35]
In addition to a vertebrate host, allPlasmodium species also infect abloodsucking insect host, generally a mosquito (although some reptile-infecting parasites are transmitted bysandflies). Mosquitoes of the generaCulex,Anopheles,Culiseta,Mansonia andAedes act as insect hosts for variousPlasmodium species. The best studied of these are theAnopheles mosquitoes which host thePlasmodium parasites of human malaria, as well asCulex mosquitoes which host thePlasmodium species that cause malaria in birds. Only female mosquitoes are infected withPlasmodium, since only they feed on the blood of vertebrate hosts.[36] Different species affect their insect hosts differently. Sometimes, insects infected withPlasmodium have reduced lifespan and reduced ability to produce offspring.[37] Further, some species ofPlasmodium appear to cause insects to prefer to bite infected vertebrate hosts over non-infected hosts.[37][38][39]
Charles Louis Alphonse Laveran first described parasites in the blood of malaria patients in 1880.[40] He named the parasiteOscillaria malariae.[40] In 1885, zoologistsEttore Marchiafava andAngelo Celli reexamined the parasite and termed it a member of a new genus,Plasmodium, named for the resemblance to themultinucleate cells ofslime molds of the same name.[41][notes 1] The fact that several species may be involved in causing different forms of malaria was first recognized byCamillo Golgi in 1886.[40] Soon thereafter,Giovanni Batista Grassi andRaimondo Filetti named the parasites causing two different types of human malariaPlasmodium vivax andPlasmodium malariae.[40] In 1897,William Welch identified and namedPlasmodium falciparum. This was followed by the recognition of the other two species ofPlasmodium which infect humans:Plasmodium ovale (1922) andPlasmodium knowlesi (identified inlong-tailed macaques in 1931; in humans in 1965).[40] The contribution of insect hosts to thePlasmodium life cycle was described in 1897 byRonald Ross and in 1899 by Giovanni Batista Grassi,Amico Bignami andGiuseppe Bastianelli.[40]
In 1966,Cyril Garnham proposed separatingPlasmodium into nine subgenera based on host specificity and parasite morphology.[18] This included four subgenera that had previously been proposed for bird-infectingPlasmodium species by A. Corradetti in 1963.[42][19] This scheme was expanded upon by Sam R. Telford in 1988 when he reclassifiedPlasmodium parasites that infect reptiles, adding five subgenera.[20][18] In 1997, G. Valkiunas reclassified the bird-infectingPlasmodium species adding a fifth subgenus:Bennettinia.[19][43]
