Plasmodium

Plasmodium is a eukaryote but with unusual features.

The genus Plasmodium consists of all eukaryotes in the phylum Apicomplexa that both undergo the asexual replication process of merogony inside host red blood cells and produce the crystalline pigment hemozoin as a byproduct of digesting host hemoglobin.[2] Plasmodium species contain many features that are common to other eukaryotes, and some that are unique to their phylum or genus. The Plasmodium genome is separated into 14 chromosomes contained in the nucleus. Plasmodium parasites maintain a single copy of their genome through much of the life cycle, doubling the genome only for a brief sexual exchange within the midgut of the insect host.[3] Attached to the nucleus is the endoplasmic reticulum (ER), which functions similarly to the ER in other eukaryotes. Proteins are trafficked from the ER to the Golgi 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 the apical end of the parasite that serve as specialized organelles for secreting effectors into the host. The most prominent are the bulbous rhoptries which contain parasite proteins involved in invading the host cell and modifying the host once inside.[5] Adjacent to the rhoptries are smaller structures termed micronemes that contain parasite proteins required for motility as well as recognizing and attaching to host cells.[6] Spread throughout the parasite are secretory vesicles called dense granules that contain parasite proteins involved in modifying the membrane that separates the parasite from the host, termed the parasitophorous vacuole.[6]

Species of Plasmodium also contain two large membrane-bound organelles of endosymbiotic origin, the mitochondrion and the apicoplast, both of which play key roles in the parasite's metabolism. Unlike mammalian cells which contain many mitochondria, Plasmodium cells contain a single large mitochondrion that coordinates its division with that of the Plasmodium cell.[7] Like in other eukaryotes, the Plasmodium mitochondrion is capable of generating energy in the form of ATP via the citric 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 a secondary endosymbiosis event, in this case the acquisition of a red alga by the Plasmodium ancestor.[8] The apicoplast is involved in the synthesis of various metabolic precursors, including fatty acids, isoprenoids, iron-sulphur clusters, and components of the heme biosynthesis pathway.[9]

Life cycle of a species that infects humans

Ring forms of Plasmodium inside human red blood cells (Giemsa stain)

The life cycle of Plasmodium involves several distinct stages in the insect and vertebrate hosts. Parasites are generally introduced into a vertebrate host by the bite of an insect host (generally a mosquito, with the exception of some Plasmodium 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 infect erythrocytes.[11] At this point, some species of Plasmodium of primates can form a long-lived dormant stage called a hypnozoite.[12] It can remain in the liver for more than a year.[13] However, for most Plasmodium 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 by Plasmodium 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 of P. vivax. These hidden parasites (in addition to hypnozoites) are thought to be the origin of instances of recurrent P. vivax malaria.[14]

Sporozoites, one of several different forms of the parasite, from a mosquito

Within the red blood cells, the merozoites grow first to a ring-shaped form and then to a larger form called a trophozoite. Trophozoites then mature to schizonts 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 the blood meal to the mosquito's midgut. Here the gametocytes develop into male and female gametes which fertilize each other, forming a zygote. Zygotes then develop into a motile form called an ookinete, 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 elongated sporozoites. 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 species are distributed globally. All Plasmodium species are parasitic and must pass between a vertebrate host and an insect host to complete their life cycles. Different species of Plasmodium 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.

Vertebrates

Many birds, from raptors to passerines like the red-whiskered bulbul (Pycnonotus jocosus), can carry malaria.

Plasmodium parasites have been described in a broad array of vertebrate hosts including reptiles, birds, and mammals.[23] While many species can infect more than one vertebrate host, they are generally specific to one of these classes (such as birds).[23]

A clinic for treating human malaria in Tanzania

Humans are primarily infected by five species of Plasmodium, with the overwhelming majority of severe disease and death caused by Plasmodium falciparum.[24] 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.[24] Non-human primates also contain a variety of Plasmodium 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.[25] Many other mammals also carry Plasmodium species, such as a variety of rodents, ungulates, and bats. Again, some species of Plasmodium can cause severe disease in some of these hosts, while many appear not to.[26]

Over 150 species of Plasmodium infect a broad variety of birds. In general each species of Plasmodium infects one to a few species of birds.[27] 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 cases Plasmodium infections can result in severe illness and rapid death.[28][29] Unlike with Plasmodium species infecting mammals, those infecting birds are distributed across the globe.[27]

Over 3000 species of lizard, including the Carolina anole (Anolis carolinensis), carry some 90 kinds of malaria.

Species from several subgenera of Plasmodium infect diverse reptiles. Plasmodium parasites have been described in most lizard families and, like avian parasites, are spread worldwide.[30] Again, parasites can result either in severe disease or be apparently asymptomatic depending on the parasite and the host.[30]

A number of drugs have been developed over the years to control Plasmodium infection in vertebrate hosts, particularly in humans. Quinine was used as a frontline antimalarial from the 17th century until widespread resistance emerged in the early 20th century.[31] Resistance to quinine spurred the development of a broad array of antimalarial medications through the 20th century including chloroquine, proguanil, atovaquone, sulfadoxine/pyrimethamine, mefloquine, and artemisinin.[31] In all cases, parasites resistant to a given drug have emerged within a few decades of the drugs deployment.[31] To combat this, antimalarial drugs are frequently used in combination, with artemisinin combination therapies currently the gold standard for treatment.[32] In general, antimalarial drugs target the life stages of Plasmodium parasites that reside within vertebrate red blood cells, as these are the stages that tend to cause disease.[33] 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.[34]

Insects

The mosquito Anopheles stephensi is among the blood-feeding insects that can be infected by a species of Plasmodium.

In addition to a vertebrate host, all Plasmodium species also infect a bloodsucking insect host, generally a mosquito (although some reptile-infecting parasites are transmitted by sandflies). Mosquitoes of the genera Culex, Anopheles, Culiseta, Mansonia and Aedes act as insect hosts for various Plasmodium species. The best studied of these are the Anopheles mosquitoes which host the Plasmodium parasites of human malaria, as well as Culex mosquitoes which host the Plasmodium species that cause malaria in birds. Only female mosquitoes are infected with Plasmodium, since only they feed on the blood of vertebrate hosts.[35] Different species affect their insect hosts differently. Sometimes, insects infected with Plasmodium have reduced lifespan and reduced ability to produce offspring.[36] Further, some species of Plasmodium appear to cause insects to prefer to bite infected vertebrate hosts over non-infected hosts.[36][37][38]

Plasmodium was first identified when Charles Louis Alphonse Laveran described parasites in the blood of malaria patients in 1880.[39] He named the parasite Oscillaria malariae.[39] In 1885, zoologists Ettore Marchiafava and Angelo Celli reexamined the parasite and termed it a member of a new genus, Plasmodium, named for the resemblance to the multinucleate cells of slime molds of the same name.[40][notes 1] The fact that several species may be involved in causing different forms of malaria was first recognized by Camillo Golgi in 1886.[39] Soon thereafter, Giovanni Batista Grassi and Raimondo Filetti named the parasites causing two different types of human malaria Plasmodium vivax and Plasmodium malariae.[39] In 1897, William Welch identified and named Plasmodium falciparum. This was followed by the recognition of the other two species of Plasmodium which infect humans: Plasmodium ovale (1922) and Plasmodium knowlesi (identified in long-tailed macaques in 1931; in humans in 1965).[39] The contribution of insect hosts to the Plasmodium life cycle was described in 1897 by Ronald Ross and in 1899 by Giovanni Batista Grassi, Amico Bignami and Giuseppe Bastianelli.[39]

In 1966, Cyril Garnham proposed separating Plasmodium into nine subgenera based on host specificity and parasite morphology.[18] This included four subgenera that had previously been proposed for bird-infecting Plasmodium species by A. Corradetti in 1963.[41][19] This scheme was expanded upon by Sam R. Telford in 1988 when he reclassified Plasmodium parasites that infect reptiles, adding five subgenera.[20][18] In 1997, G. Valkiunas reclassified the bird-infecting Plasmodium species adding a fifth subgenus: Bennettinia.[19][42]

• Plasmodium molecular tools
• List of Plasmodium species
• Haematozoa

Wikispecies has information related to Plasmodium.

Wikimedia Commons has media related to Plasmodium.

• Malaria Atlas Project
• Plasmodium lifecycle animation