PLASMODIUM

HISTORY

The organism itself was first seen by Laveran on November 6, 1880 at a military hospital in Constantine, Algeria, when he discovered a microgametocyte exflagellating. In 1885, similar organisms were discovered within the blood of birds in Russia. There was brief speculation that birds might be involved in the transmission of malaria; in 1894 Patrick Manson hypothesized that mosquitoes could transmit malaria. This hypothesis was independently confirmed by the Italian physician Giovanni Battista Grassi working in Italy and the British physician Ronald Ross working in India, both in 1898. Ross demonstrated the existence of Plasmodium in the wall of the midgut and salivary glands of a Culex mosquito using bird species as the vertebrate host. For this discovery he won the Nobel Prize in 1902. Grassi showed that human malaria could only be transmitted by Anopheles mosquitoes. It is worth noting, however, that for some species the vector may not be a mosquito.

BIOLOGY

The genome of four Plasmodium species—Plasmodium falciparum, Plasmodium knowlesi, Plasmodium vivax, and Plasmodium yoelii—have been sequenced. All these species have genomes of about 25 megabases organised into 14 chromosomes consistent with earlier estimates. The chromosomes vary in length from 500 kilobases to 3.5 megabases and it is presumed that this is the pattern throughout the genus. The plasmodium contains a degenerated chloroplast called an apicoplast. Due to this it is sensitive to herbicides. The biology of these organisms is more fully described at Plasmodium falciparum biology.

DIAGNOSTICS CHARACTERISTICS

Merogony occurs both in erythrocytes and other tissues Merozoites, schizonts or gametocytes can be seen within erythrocytes and may displace the host nucleus Merozoites have a "signet-ring" appearance due to a large vacuole that forces the parasite’s nucleus to one pole Schizonts are round to oval inclusions that contain the deeply staining merozoites Forms gamonts in erythrocytes Gametocytes are 'halter-shaped' similar to Haemoproteus but the pigment granules are more confined Hemozoin is present Vectors are either mosquitos or sandflies Vertebrate hosts include mammals, birds and reptiles.

LIFE CYCLE

The life cycle of Plasmodium while complex is similar to several other species in the Haemosporidia. All the Plasmodium species causing malaria in humans are transmitted by mosquito species of the genus Anopheles. Species of the mosquito genera Aedes, Culex, Culiseta, Mansonia and Theobaldia can also transmit malaria but not to humans. Bird malaria is commonly carried by species belonging to the genus Culex. The life cycle of Plasmodium was discovered by Ross who worked with species from the genus Culex. Both sexes of mosquitos live on nectar. Because nectar's protein content alone is insufficient for oogenesis (egg production) one or more blood meals is needed by the female. Only female mosquitoes bite. Sporozoites from the saliva of a biting female mosquito are transmitted to either the blood or the lymphatic system of the recipient. It has been known for some time now that the parasites block the salivary ducts of the mosquito and as a consequence the insect normally requires multiple attempts to obtain blood. The reason for this has not been clear. It is now known that the multiple attempts by the mosquito may contribute to immunological tolerance of the parasite. The majority of sporozoites appear to be injected into the subcutaneous tissue from which they migrate into the capillaries. A proportion are ingested by macrophages and still others are taken up by the lymphatic system where they are presumably destroyed. ~10% of the parasites inoculated by the mosquitoes may remain in the skin where they may develop into infective merozoites.

DENDRITIC CELLS

It is known that the murine parasites can infect, survive and replicate within plasmacytoid dendritic cells of the spleen and that these infections may be productive. The importance of this site of replication in mice has yet to be established and it is currently unknown if these cells support parasite replication in other species.

HEPATIC STAGES

The majority of sporozoites migrate to the liver and invade hepatocytes. For reasons that are currently unclear each sporozoite typically penetrates several hepatocytes before choosing one to reside within. Once the sporozoite has ceased migration it undergoes an initial remodelling of the pellicle, with disassembly of the inner membrane complex and the appearance of a bulb that progressively enlarges until the initially elongated sporozoite has transformed into a rounded form. This rounded form then matures within the hepatocyte to a schizont containing many merozoites. In some Plasmodium species, such as Plasmodium vivax and Plasmodium ovale, the parasite in the hepatocyte may not achieve maturation to a schizont immediately but remain as a latent or dormant form and called a hypnozoite. Although Plasmodium falciparum is not considered to have a hypnozoite form, this may not be entirely correct (vide infra). This stage may be as short as 48 hours in the rodent parasites and as long as 15 days in P. malariae in humans. There is considerable variation in the appearance of the blood forms between individuals experimentally inoculated at the same time. Even within a single experimentally individual there may be considerable variation in the maturity of the hepatic forms seen on liver biopsy. A proportion of the hepatic stages may remain within the liver for considerable time - a form known as hypnozoites. Reactivation of the hypnozoites has been reported for up to 30 years after the initial infection in humans. The factors precipating this reactivation are not known. In the species Plasmodium ovale and Plasmodium vivax, but not in Plasmodium malariae, hypnozoites have been shown to occur. It is not yet known if hypnozoite reactivaction occurs with any of the remaining species that infect humans but this is presumed to be the case. The development from the hepatic stages to the erythrocytic stages has, until very recently, been obscure. In 2006 it was shown that the parasite buds off the hepatocytes in merosomes containing hundreds or thousands of merozoites. These merosomes lodge in the pulmonary capillaries and slowly disintegrate there over 48–72 hours releasing merozoites. The membrane of the merosome is derived from the host hepatocyte. The membrane of the merozoites is formed by repeated invagination of the parasite's membrane. The parastitophorus vacuole breaks down within the hepatocyte. This is associated with degeneration of the host cell's mitochondria and cessation of protein synthesis which is probably due to the lack of mitochondially produced ATP. The membrane of the merosome is then formed from that of the hepatocyte membrane but the hepatocyte proteins within the membrane are lost. This host derived membrane presumably provides protection from the immune system while the merozoites are transported to the lung. Erythrocyte invasion is enhanced when blood flow is slow and the cells are tightly packed: both of these conditions are found in the alveolar capillaries. Infection of the liver may be influenced by the iron regulatory hormone hepcidin and this may play a role in preventing superinfection despite repeated inoculation.

ERYTHROCYTE STAGES

After entering the erythrocyte, the merozoite lose one of their membranes, the apical rings, conoid and the rhopteries. Phagotropy commences and both smooth and granular endoplasmic reticulum becomes prominent. The nucleus may become lobulated. Within the erythrocytes the merozoite grow first to a ring-shaped form and then to a larger trophozoite form. In the schizont stage, the parasite divides several times to produce new merozoites, which leave the red blood cells and travel within the bloodstream to invade new red blood cells. The parasite feeds by ingesting haemoglobin and other materials from red blood cells and serum. The feeding process damages the erythrocytes. Details of this process have not been studied in species other than Plasmodium falciparum so generalizations may be premature at this time. Erythrocytes infected by Plasmodium falciparum tend to form clumps - rosettes - and these have been linked to pathology caused by vascular occlusion. This rosette formation may be inhibted by heparin. This agent has been used in the past as part of the treatment of malaria but was abandoned because of an increased risk of haemorrhage. Low molecular weight heparin also disrupts rosette formation and may have a lower risk of bleeding in malaria. Rosetting has been shown to be due to the binding of the erythrocyte major protein (the var gene product) to the ABO blood group protein. Blood group A is preferred over group B which in turn is preferred over group O. This has been shown to be due to different fits of blood group protein to the erythrocyte major protein. The binding side on the erythrocyte major protein is opposite to the heparin binding site on the same protein. Although the ABO blood group is associated with severe malaria this association is lost in pregnancy. The regulation of the erythrocyte stages is poorly understood. It is known that melatonin plays a role but how this affects the parasite is only slowly being worked out. It seems that melatonin affects the ubiquitin/proteasome system and a protein kinase (PfPK7) are central to this process. The presence of the parasite within the erythrocyte increases the membrane stiffness. This may be due to an increase in the cross linking of the intraerythrocytic spectrin network or simply due to the mechanical effects of the presence of the parasite itself within the cell.

MEROZOITES

The budding of the merozoites from interconnected cytoplasmic masses (pseudocytomeres) is a complex process. At the tip of each bud a thickened region of pellicle gives rise to the apical rings and conoid. As development proceeds an aggregation of smooth membranes and the nucleus enter the base of the bud. The cytoplasm contains numerous large ribosomes. Synchronous multiple cytoplasmic cleavage of the mature schizont results in the formation of numerous uninucleate merozoites. Escape of the merozoites from the erythrocyte has also been studied. The erythrocyte swells under osmotic pressure. A pore opens in the erythrocte membrane and 1-2 meorozites escape. This is followed by an eversion the entire erythrocyte membrane, an action that propels the merozoites into the blood stream. Invasion of erythrocyte precursors has only recently been studied. The earliest stage susceptible to infection were the orthoblasts - the stage immediately preceding the reticulocyte stage which in turn is the immediate precursor to the mature erythrocyte. Invasion of the erythrocyte is inhibited by angiotensin 2 Angiotensin 2 is normally metabolized by erythrocytes to angiotensin (Ang) IV and Ang-(1-7). Parasite infection decreased the Ang-(1-7) levels and completely abolished Ang IV formation. Ang-(1-7), like its parent molecule, is capable of decreasing the level of infection. The mechanism of inhibition seems likely to be an inhibition of protein kinase A activity within the erythrocyte.

PLACENTAL MALARIA

More than a hundred late-stage trophozoites or early schizont infected erythrocytes of P. falciparum in a case of placental malaria of a Tanzanian woman were found to form a nidus in an intervillous space of placenta. While such a concentration of parasites in placental malaria is rare, placental malaria cannot give rise to persistent infection as pregnancy in humans normally lasts only 9 months.

GAMETOCYTES

Most merozoites continue this replicative cycle but some merozoites differentiate into male or female sexual forms (gametocytes) (also in the blood), which are taken up by the female mosquito. This process of differentiation into gametocytes appears to occur in the bone marrow. Five distinct morphological stages have recognised (stages I - V). Female gametocytes are produced about four times as commonly as male. In chronic infections in humans the gametocytes are often the only forms found in the blood. Incidentally the characteristic form of the female gametocytes in Plasmodium falciparum gave rise to this species's name. Gameteocytes appear in the blood after a number of days post infection. In P. falciparum infections they appear after 7 to 15 days while in others they appear after 1 to 3 days. The ratio of asexual to sexual forms is between 10:1 and 156:1 The half life of the gametocytes has been estimated to be between 2 and 3 days but some are known to persist for up to four weeks. Gametocyte carriage is associated with anaemia. Although female gametocytes normally outnumber males this may be reversed in the presence of anaemia. The adhesive properties of the gametocytes have rarely been investigated but they appear to differ from the asexual forms in their adhesive properties. Stage V gametocytes do not show any appreciable binding, consistent with their condition of being freely circulating cells. The mechanisms involved in the maturation and release of the gametocytes from the bone marrow are still under investigation. The mature gametocyte infected cells are more deformable than the immature and this is associated with the de association of the STEVOR proteins from the host cell membrane. It may be that mechanical retention contributes to sequestration of immature gametocytes and that the regained deformability of mature gametocytes is associated with their release in the bloodstream and ability to circulate.

GAMETOCYTE MORPHOLOGY

The five recognised morphological stages were first described by Field and Shute in 1956. One constant feature of the gametocytes in all stages that distinguishes them from the asexual forms is the presence of a pellicular complex. This originates in small membranous vesicle observed beneath the gametocyte plasmalemma in late stage I. Its function is not known. The structure itself consists of a subpellicular membrane vacuole. Deep to this is an array of longitudinally oriented microtubules. This structure is likely to be relatively inflexible and may help to explain the lack of amoeboid forms observed in asexual parasites. Gametocyte elongation is driven by the assembly of a system of flattened cisternal membrane compartments underneath the parasite plasma membrane and has a supporting network of microtubules. The sub-pellicular membrane complex is analogous to the inner membrane complex, an organelle with structural and motor functions that is well conserved across the apicomplexa. Early stage one gametoctyes are very difficult to distinguish from small round trophozoites. Later stages can be distinguished by the distribution of pigment granulues. Under the electrom microscope the formation of the subpellicular membrane and a smooth plasma membrane are recognisable. The nuclei are recognisably dimorphic into male and female. These forms may be found between day 0 and day 2 in P falciparum infections. In stage two the gametocyte enlarges and becomes D shaped. The nucleus may occupy a terminal end of the cell or lie along its length. Early spindle formation may be visible. These forms are found between day 1 to day 4 in P falciparum infections. In stage three the erythrocyte becomes distorted. A staining difference between the male and female gametoctyes is apparent (male stain pink while female stain faint blue with the usual stains). The male nucleus is noticeably larger than the female and more lobulated. The female cytoplasm has more ribosomes, endoplasmic reticulum and mitochondria. Electron dense organelles (osmophilic bodies) are found in both sexes but are more numerous in the female. The osmophilic bodies are thought to be involved in egress of the gametocyte from the erythrocyte. These organelles are found between day 4 and day 10 in P. falciparum infections. They are connected to the gametocyte surface by ducts and are almost absent after transformation into the female gamete. In stage four the erythrocyte is clearly deformed and the gametocyte is elongated. The male gametocytes stain red while the female stain violet blue. In the male pigment granules are scattered while in the female they are more dense. In the male the kinetochores of each chromosome are located over a nuclear pore. In stage five the gametocytes are clearly recognisable on light microscopy with the typical banana shaped female gametocytes. The subpellicular microtubules depolymerise but the membrane itself remains. In the male gametocyte exhibit the is a dramatic reduction in ribosomal density. Very few mitochondria are retained and the nucleus enlarges with a kinetochore complex attached to the nuclear envelope. In the female gametocytes there are numerous mitochondria, ribosomes and osmophillic bodies. The nucleus is small with a transcription factory. Stages other than stage five are not normally found in the periferal blood. For reasons not yet understood stages I to IV are sequestered preferentially in the bone marrow and spleen. Stage V gametocytes only become infectious to mosquitoes after a further two or three days of circulation.

INFECTION OF MOSQUITO

In the mosquito's midgut, the gametocytes develop into gametes: the process of activation and gametogenesis occur within 15 minutes of ingestion. and fertilize each other resulting in formation of a diploid zygote: this usually occurs within one hour of ingestion. Zygotes immediately undergo meiosis and differentiate within 24 hours of ingestion into motile, invasive ookinetes. It has been shown that up to 50% of the ookinetes may undergo apoptosis within the midgut. The reason for this behavior is unknown. While in the mosquito gut the parasites form thin cytoplasmic extensions to communicate with each other. These structures persist from the time of gametocyte activation until the zygote transforms into an ookinete. The function of these tubular structures remains to be discovered. The ookinetes penetrate the midgut epithelium and escape the midgut, then attach themselves onto the exterior of the gut membrane beneath the basal lamina where they differentiate into oocysts. As in the liver the parasite tends to invade a number of cells before choosing one to reside in. The reason for this behavior is not known. Here they divide many times (usually 11) to produce large numbers (8,000) of tiny elongated sporozoites. These sporozoites migrate to the salivary glands of the mosquito where they are injected into the blood and subcutaneous tissue of the next host the mosquito bites. The invasion process appears to be dependent on a serine protease produced by the mosquito in the midgut epithelial cells and in the basal side of the salivary glands. The escape of the gametocytes from the erythrocytes has been until recently obscure. The parasitophorous vacuole membrane ruptures at multiple sites within less than a minute following ingestion. This process may be inhibited by cysteine protease inhibitors. After this rupture of the vacuole the subpellicular membrane begins to disintegrate. This process also can be inhibited by aspartic and the cysteine/serine protease inhibitors. Approximately 15 minutes post-activation, the erythrocyte membrane ruptures at a single breaking point a third process that can be interrupted by protease inhibitors. Effects on the mosquito Infection of the mosquito has noticeable effects on the host. The presence of the parasite induces apoptosis of the egg follicles. The development of the parasite in the mosquito is temperature dependent with higher temperatures being associated with more rapid development. Higher temperatures appear to enhance the mosquito's immune system leading to a lower average infection rate. Survival of infected mosquitoes is enhanced in starvation conditions compared to uninfected controls. Development within the mosquito involves several insulin like peptides. Blocking this pathway results in reduced parasite development. It appears that the parasite is capable of altering the physiology of the mosquito host and this alternation under starvation conditions is favourable to the host. Infection appears to reduce fecundity (ability to reproduce) and to increase survival of the mosquito. This is in line with what evolutionary theory would predict.

DISCUSSION

A report of P. falciparum malaria in a patient with sickle cell anemia four years after exposure to the parasite has been published. A second report that P. falciparum malaria had become symptomatic eight years after leaving an endemic area has also been published. A third case of an apparent recurrence nine years after leaving an endemic area of P. falciparum malaria has now been reported. A fourth case of recurrence in a patient with lung cancer has been reported. Two cases in pregnant women both from Africa but who had not lived there for over a year have been reported. A case of congenital malaria due to both P. falciparum and P. malariae has been reported in a child born to a woman from Ghana, a malaria endemic area, despite the mother having emigrated to Austria eighteen months before and never having returned. A second case of congenital malaria in twins due to P. falciparum has been reported. The mother had left Togo 14 months before the diagnosis, had not returned in the interim and was never diagnosed with malaria during her pregnancy. One case of malaria has been reported in a man of African origin with sickle cell trait who was treated for B cell lymphoma with chemotherapy and an autologous bone marrow transplant. He developed symptomatic malaria only after a subsequent splenectomy performed for worsening disease. Pre treatment blood films and antigen testing were negative. It seems that at least occasionally P. falciparum has a dormant stage. If this is in fact the case, eradication or control of this organism may be more difficult than previously believed.

DORMANT FORMS

PLASMODIUM FALCIPARUM MALARIA

PLASMODIUM MALARIAE

This parasite is not thought to have a latent form but relapses have been reported. The mechanism here is not yet clear.

DRUG INDUCED

Developmental arrest was induced by in vitro culture of P. falciparum in the presence of sub lethal concentrations of artemisinin. The drug induces a subpopulation of ring stages into developmental arrest. At the molecular level this is associated with overexpression of heat shock and erythrocyte binding surface proteins with the reduced expression of a cell-cycle regulator and a DNA biosynthesis protein. The schizont stage-infected erythrocyte in an experimental culture of P. falciparum, F32 was suppressed to a low level with the use of atovaquone. The parasites resumed growth several days after the drug was removed from the culture.

BIOLOGICAL REFUGES

Macrophages containing merozoites dispersed in their cytoplasm, called 'merophores', were observed in P. vinckei petteri - an organism that causes murine malaria. Similar merophores were found in the polymorph leukocytes and macrophages of other murine malaria parasite, P. yoelii nigeriensis and P. chabaudi chabaudi. All these species unlike P. falciparum are known to produce hyponozoites that may cause a relapse. The finding of Landau et al. on the presence of malaria parasites inside lymphatics suggest a mechanism for the recrudescence and chronicity of malaria infection.

EVOLUTION

As of 2007, DNA sequences are available from less than sixty species of Plasmodium and most of these are from species infecting either rodent or primate hosts. The evolutionary outline given here should be regarded as speculative, and subject to revision as more data becomes available.

APICOMPLEXA

The common ancestor of the Alveolates - a clade to which the Apicomplexa belong - was a myzocytotic predator with two heterodynamic flagella, micropores, trichocysts, rhoptries, micronemes, a polar ring and a coiled open sided conoid. The Alveolates have lost the axonemal locomotive structures found in the other members of this clade except in gametes. The ancestor of this group seems likely to have had some photosynthetic ability. A recently identified apicomplexan found in Australian corals - Chromera velia - has retained a photosynthetic plastid. It appears that the alveolates, the dinoflagellates and the heterokont algae acquired their plastids from a red algae suggesting a common origin of this organelle in all these clades. Many of the species within the Apicomplexia still possess plastids (the organelle in which photosynthesis occurs in photosynthetic eukaryotes) and some that lack plastids nonetheless have evidence of plastid genes within their genomes. Some extant dinoflagellates can invade the bodies of jellyfish and continue to photosynthesize, which is possible because jellyfish bodies are almost transparent. In host organisms with opaque bodies, such an ability would most likely rapidly be lost. In the majority of such species, the plastids are not capable of photosynthesis. Their function is not known, but there is suggestive evidence that they may be involved in reproduction. All sequenced mitochondrial genomes of ciliates and apicomplexia are linear. Whether this is true for the related clades is not yet known. The mitochondrial genome has undergone a severe reduction in size in the Alveolate clade. In the Apicomplexa, where mitochondrion is present, its genome has only three genes (In Cryptosporidium the mitochondion has been lost entirely.) The dinoflagellate mitochondia also have only the same three genes. In Colpodella - a relative of the Apicomplexa - the mitochondrial genome has but a single gene. Since the known ciliate mitochondrial genomes are considerably larger this reduction is genome size must have occurred after their ancestor of this clade diverged from that that gave rise to the extant ciliates. Why this reduction has occurred it not presently clear.

PLASMODIUM GENUS

Current (2007) theory suggests that the genera Plasmodium, Hepatocystis and Haemoproteus evolved from one or more Leucocytozoon species. Parasites of the genus Leucocytozoan infect white blood cells (leukocytes) and liver and spleen cells, and are transmitted by 'black flies' (Simulium species) — a large genus of flies related to the mosquitoes. It is thought that Leucocytozoon evolved from a parasite that spread by the orofaecal route and which infected the intestinal wall. At some point this parasite evolved the ability to infect the liver. This pattern is seen in the genus Cryptosporidium, to which Plasmodium is distantly related. At some later point this ancestor developed the ability to infect blood cells and to survive and infect mosquitoes. Once vector transmission was firmly established, the previous orofecal route of transmission was lost. The pattern of orofaecal transmission with coincidental infection of the erythrocytes is seen in the genus Schellackia. Species in this genus infect lizards. The usual route of transmission is orofaecal but the parasites can also infect erythrocytes if they traverse the intestinal wall. The infected erythrocytes may be ingested by mites. These infected mites may subsequently be eaten by other uninfected lizards whereupon the parasites emerge and infect these new hosts. Unlike Plasmodium no development occurs in the mite. Molecular evidence suggests that a reptile - specifically a squamate - was the first vertebrate host of Plasmodium. Birds were the second vertebrate hosts with mammals being the most recent group of vertebrates infected. Leukocytes, hepatocytes and most spleen cells actively phagocytose particulate matter, which makes the parasite's entry into the cell easier. The mechanism of entry of Plasmodium species into erythrocytes is still very unclear, as it takes place in less than 30 seconds. It is not yet known if this mechanism evolved before mosquitoes became the main vectors for transmission of Plasmodium. The genus Plasmodium evolved (presumably from its Leucocytozoon ancestor) about 130 million years ago, a period that is coincidental with the rapid spread of the angiosperms (flowering plants). This expansion in the angiosperms is thought to be due to at least one gene duplication event. It seems probable that the increase in the number of flowers led to an increase in the number of mosquitoes and their contact with vertebrates.

VECTORS

Mosquitoes evolved in what is now South America about 230 million years ago. There are over 3500 species recognized, but to date their evolution has not been well worked out, so a number of gaps in our knowledge of the evolution of Plasmodium remain. There is evidence of a recent expansion of Anopheles gambiae and Anopheles arabiensis populations in the late Pleistocene in Nigeria. The reason why a relatively limited number of mosquitoes should be such successful vectors of multiple diseases is not yet known. It has been shown that, among the most common disease-spreading mosquitoes, the symbiont bacterium Wolbachia are not normally present. It has been shown that infection with Wolbachia can reduce the ability of some viruses and Plasmodium to infect the mosquito, and that this effect is Wolbachia-strain specific.

CLASSIFICATION

TAXONOMY

Plasmodium belongs to the family Plasmodiidae (Levine, 1988), order Haemosporidia and phylum Apicomplexa. There are currently 450 recognised species in this order. Many species of this order are undergoing reexamination of their taxonomy with DNA analysis. It seems likely that many of these species will be re-assigned after these studies have been completed. For this reason the entire order is outlined here.

Order Haemosporida

Family Haemoproteidae
Genus Haemocystidium Castellani and Willey 1904, emend. Telford 1996 Genus Haemoproteus Subgenus Parahaemoproteus Subgenus Haemoproteus Family Garniidae
Genus Fallisia Lainson, Landau & Shaw 1974 Subgenus Fallisia Subgenus Plasmodioides Genus Garnia Genus Progarnia Family Leucocytozoidae
Genus Leucocytozoon Subgenus Leucocytozoon Subgenus Akiba Family Plasmodiidae
Genus Bioccala Genus Billbraya Genus Dionisia Genus Hepatocystis Genus Mesnilium Genus Nycteria Genus Plasmodium Subgenus Asiamoeba Telford 1988 Subgenus Bennettinia Valkiunas 1997 Subgenus Carinamoeba Garnham 1966 Subgenus Giovannolaia Corradetti, Garnham & Laird 1963 Subgenus Haemamoeba Grassi & Feletti 1890 Subgenus Huffia Garnham & Laird 1963 Subgenus Lacertaemoba Telford 1988 Subgenus Laverania Bray 1963 Subgenus Novyella Corradetti, Garnham & Laird 1963 Subgenus Ophidiella Garnham 1966 Subgenus Papernaia Landau et al 2010 Subgenus Plasmodium Bray 1963 emend. Garnham 1964 Subgenus Paraplasmodium Telford 1988 Subgenus Sauramoeba Garnham 1966 Subgenus Vinckeia Garnham 1964 Genus Polychromophilus Genus Rayella Genus Saurocytozoon Genus Vetufebrus Poinar 2011

PHYLOGENETIC TREES

The relationship between a number of these species can be seen on the Tree of Life website. Perhaps the most useful inferences that can be drawn from this phylogenetic tree are: P. falciparum and P. reichenowi (subgenus Laverania) branched off early in the evolution of this genus The genus Hepatocystis is nested within (paraphytic with) the genus Plasmodium The primate (subgenus Plasmodium) and rodent species (subgenus Vinckeia) form distinct groups The rodent and primate groups are relatively closely related The lizard and bird species are intermingled Although Plasmodium gallinaceum (subgenus Haemamoeba) and Plasmodium elongatum (subgenus Huffia) appear be related here there are so few bird species (three) included, this tree may not accurately reflect their real relationship. While no snake parasites have been included these are likely to group with the lizard-bird division While this tree contains a considerable number of species, DNA sequences from many species in this genus have not been included - probably because they are not available yet. Because of this problem, this tree and any conclusions that can be drawn from it should be regarded as provisional. Three additional trees are available from the American Museum of Natural History. These trees agree with the Tree of Life. Because of their greater number of species in these trees, some additional inferences can be made: The genus Hepatocystis appears to lie within the primate-rodent clade The genus Haemoproteus appears lie within the bird-lizard clade The trees are consistent with the proposed origin of Plasmodium from Leucocytozoon It is also known that the species infecting humans do not form a single clade. In contrast, the species infecting Old World monkeys seem to form a clade. Plasmodium vivax may have originated in Asia and the related species Plasmodium simium appears to be derived through a transfer from the human P. vivax to New World monkey species in South America. This occurred during an indepth study of Howler Monkeys near São Paulo, Brasil. Another tree concentrating on the species infecting the primates is available here: PLOS site This tree shows that the 'African' (P. malaria and P. ovale) and 'Asian' (P.cynomogli, P. gonderi, P. semiovale and P. simium) species tend to cluster together into separate clades. P. vivax clusters with the 'Asian' species. The rodent species (P. bergei, P. chabaudi and P. yoelli) form a separate clade. As usual P. falciparum does not cluster with any other species. The bird species (P. juxtanucleare, P. gallinaceum and P. relictum) form a clade that is related to the included Leucocytozoon and Haemoproteus species. A second tree can be found on the PLoS website: PLOS site This tree concentrates largely on the species infecting primates. The three bird species included in this tree (P. gallinacium, P. juxtanucleare and P. relictum) form a clade. Four species (P. billbrayi, P. billcollinsi, P. falciparum and P. reichenowi) form a clade within the subgenus Lavernia. This subgenus is more closely related to the other primate species than to the bird species or the included Leuocytozoan species. Both P. billbrayi and P. billcollinsi infect both the chimpanzee subspecies included in this study (Pan troglodytes troglodytes and Pan troglodytes schweinfurthii). P. falciparum infects the bonbo (Pan paniscus) and P. reichenowi infects only one subspecies (Pan troglodytes troglodytes). The eleven 'Asian' species included here form a clade with P. simium and P. vivax being clearly closely related as are P. knowseli and P. coatneyi; similarly P. brazillium and P. malariae are related. P. hylobati and P. inui are closely related. P. fragile and P. gonderi appear to be more closely related to P. vivax than to P. malariae. P. coatneyi and P. inui appear to be closely related to P. vivax. P. ovale is more closely related to P. malariae than to P. vivax. Within the 'Asian' clade are three unnamed potential species. One infects each of the two chimpanzee subspecies included in the study (Pan troglodytes troglodytes and Pan troglodytes schweinfurthii). These appear to be related to the P. vivax/P. simium clade. Two unnamed potential species infect the bonbo (Pan paniscus) and these are related to the P. malariae/P. brazillium clade.

NOTES

An analysis of ten 'Asian' species (P. coatneyi, P. cynomolgi, P. fieldi, P. fragile, P. gonderi, P. hylobati, P. inui, P. knowlesi, P. simiovale and P. vivax) suggests that P. coatneyi and P. knowlesi are closely related and that P. fragile is the species most closely related to these two. P. vivax and P. cynomolgi appear to be related. Unlike other eukaryotes studied to date Plasmodium species have two or three distinct SSU rRNA (18S rRNA) molecules encoded within the genome. These have been divided into types A, S and O. Type A is expressed in the asexual stages; type S in the sexual and type O only in the oocyte. Type O is only known to occur in Plasmodium vivax at present. The reason for this gene duplication is not known but presumably reflects an adaption to the different environments the parasite lives within. The Asian simian Plasmodium species - Plasmodium coatneyi, Plasmodium cynomolgi, Plasmodium fragile, Plasmodium inui, Plasmodium fieldi, Plasmodium hylobati and Plasmodium simiovale - have a single S-type-like gene and several A-type-like genes. It seems likely that these species form a clade within the subgenus Plasmodium. Analysis of the merozoite surface protein in ten species of the Asian clade suggest that this group diversified between 3 and 6.3 million years ago - a period that coincided with the radiation of the macques within South East Asia. The inferred branching order differs from that found from the analysis of other genes suggesting that this phylogenetic tree may be difficult to resolve. Positive selection on this gene was also found. P. vivax appears to have evolved between 45,000 and 82,000 years ago from a species that infects south east Asian macques. This is consistent with the other evidence of a south eastern origin of this species. It has been reported that the C terminal domain of the RNA polymerase 2 in the primate infecting species (other than P. falciparum and probably P. reichenowei) appears to be unusual suggesting that the classification of species into the subgenus Plasmodium may have an evolutionary and biological basis. A report of a new species that clusters with P. falciparum and P. reichenowi in chimpanzees has been published, although to date the species has been identified only from the sequence of its mitochondrion. Further work will be needed to describe this new species, however, it appears to have diverged from the P. falciparum- P. reichenowi clade about 21 million years ago. A second report has confirmed the existence of this species in chimpanzees. This report has also shown that P. falciparum is not a uniquely human parasite as had been previously believed. A third report of P. falciparum has been published. This study investigated two mitochondrial genes (cytB and cox1), one plastid gene (tufA), and one nuclear gene (ldh) in 12 chimpanzees and two gorillas from Cameroon and one lemur from Madagascar. Plasmodium falciparum was found in one gorilla and two chimpanzee samples. Two chimpanzee samples tested positive for Plasmodium ovale and one for Plasmodium malariae. Additionally one chimpanzee sample showed the presence of P. reichenowi and another P. gaboni. A new species - Plasmodium malagasi - was provisionally identified in the lemur. This species seems likely to belong to the Vinckeia subgenus but further work is required. A study of ~3000 wild ape specimens collected from Central Africa has shown that Plasmodium infection is common and is usually with multiple species.[85] The ape species included in the study were western gorillas (Gorilla gorilla), eastern gorillas (Gorilla beringei), bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). 99% of the strains fell into six species within the subgenus Laverina. P. falciparum formed a monophyletic lineage within the gorilla parasite radiation suggesting an origin in gorrilas rather than chimpanzees. It has been shown that P. falciparum forms a clade with the species P reichenowi.[86] This clade may have originated between 3 million and 10000 years ago. It is proposed that the origin of P. falciparum may have occurred when its precursors developed the ability to bind to sialic acid Neu5Ac possibly via erythrocyte binding protein 175. Humans lost the ability to make the sialic acid Neu5Gc from its precursor Neu5Ac several million years ago and this may have protected them against infection with P. reichenowi. The dates of the evolution of the species within the subgenus Laverania have been estimated as follows:
Laverania: 12.0 million years ago (Mya) (95% estimated range: 6.0 - 19.0 Mya) P. falciparum in humans: 0.2 Mya (range: 0.078 - 0.33 Mya) P. falciparum in Pan paniscus: 0.77 Mya (range: 0.43 - 1.6 Mya) P. falciparum in humans and Pan paniscus: 0.85 Mya (0.46 - 1.3 Mya) P. reichenowi - P. falciparum in Pan paniscus: 2.2 Mya (range: 1.0 - 3.1 Mya) nd that P. reichenowi - 1.8 Mya (range: 0.6 - 3.2 Mya) P. billbrayi - 1.1 Mya (range: 0.52 - 1.7 Mya) lciparum P. billcollinsi - 0.97 Mya (range: 0.38 - 1.7 Mya) Another estimation of the date of evolution of this genus based upon the mutation rate in the cytochrome b gene places the evolution of P. falciparum at 2.5 Mya. The authors also estimated that the mammalian species of this genus evolved 12.8 Mya and that the order Haemosporida evolved 16.2 Mya. While the date of evolution of P. falciparum is consistent with alternative methods, the other two dates are considerably more recent than other published estimates and probably should be treated with caution. Plasmodium ovale has recently been shown to consist of two cocirculating species - Plasmodium ovale curtisi and Plasmodium ovale wallikeri. These two species can only be distinguished by genetic means and they separated between 1.0 and 3.5 million years ago. A recently (2009) described species (Plasmodium hydrochaeri) that infects capybaras (Hydrochaeris hydrochaeris) may complicate the phylogentics of this genus. This species appears to be most similar to Plasmodium mexicanum a lizard parasite. Further work in this area seems indicated.

SUBGENERA

The full taxonomic name of a species includes the subgenus but this is often omitted. The full name indicates some features of the morphology and type of host species. Sixteen subgenera are currently recognised. The avian species were discovered soon after the description of P. falciparum and a variety of generic names were created. These were subsequently placed into the genus Plasmodium although some workers continued to use the genera Laverinia and Proteosoma for P. falciparum and the avian species respectively. The 5th and 6th Congresses of Malaria held at Istanbul (1953) and Lisbon (1958) recommended the creation and use of subgenera in this genus. Laverinia was applied to the species infecting humans and Haemamoeba to those infecting lizards and birds. This proposal was not universally accepted. Bray in 1955 proposed a definition for the subgenus Plasmodium and a second for the subgenus Laverinia in 1958. Garnham described a third subgenus - Vinckeia - in 1964.

MAMMAL INFECTING SPECIES

Two species in the subgenus Laverania are currently recognised: P. falciparum and P. reichenowi. Three additional species - Plasmodium billbrayi, Plasmodium billcollinsi and Plasmodium gaboni - may also exist (based on molecular data) but a full description of these species have not yet been published. The presence of elongated gametocytes in several of the avian subgenera and in Laverania in addition to a number of clinical features suggested that these might be closely related. This is no longer thought to be the case. The type species is Plasmodium falciparum. Species infecting monkeys and apes (the higher primates) other than those in the subgenus Laverania are placed in the subgenus Plasmodium. The position of the recently described Plasmodium GorA and Plasmodium GorB has not yet been settled. The distinction between P. falciparum and P. reichenowi and the other species infecting higher primates was based on the morphological findings but have since been confirmed by DNA analysis. The type species is Plasmodium malariae. Parasites infecting other mammals including lower primates (lemurs and others) are classified in the subgenus Vinckeia. Vinckeia while previously considered to be something of a taxonomic 'rag bag' has been recently shown - perhaps rather surprisingly - to form a coherent grouping. The type species is Plasmodium bubalis.

BIRD INFECTING SPECIES

The remaining groupings are based on the morphology of the parasites. Revisions to this system are likely to occur in the future as more species are subject to analysis of their DNA. The four subgenera Giovannolaia, Haemamoeba, Huffia and Novyella were created by Corradetti et al. for the known avian malarial species. A fifth—Bennettinia—was created in 1997 by Valkiunas. The relationships between the subgenera are the matter of current investigation. Martinsen et al. 's recent (2006) paper outlines what is currently (2007) known. The subgenera Haemamoeba, Huffia, and Bennettinia appear to be monphylitic. Novyella appears to be well defined with occasional exceptions. The subgenus Giovannolaia needs revision. P. juxtanucleare is currently (2007) the only known member of the subgenus Bennettinia. Nyssorhynchus is an extinct subgenus of Plasmodium. It has one known member - Plasmodium dominicum

REPTILE INFECTING SPECIES

Unlike the mammalian and bird malarias those species (more than 90 currently known) that infect reptiles have been more difficult to classify. In 1966 Garnham classified those with large schizonts as Sauramoeba, those with small schizonts as Carinamoeba and the single then known species infecting snakes (Plasmodium wenyoni) as Ophidiella. He was aware of the arbitrariness of this system and that it might not prove to be biologically valid. Telford in 1988 used this scheme as the basis for the currently accepted (2007) system. These species have since been divided in to 8 genera - Asiamoeba, Carinamoeba, Fallisia, Garnia, Lacertamoeba, Ophidiella, Paraplasmodium and Sauramoeba. Three of these genera (Asiamoeba, Lacertamoeba and Paraplasmodium) were created by Telford in 1988. Another species (Billbraya australis) described in 1990 by Paperna and Landau and is the only known species in this genus. This species may turn out to be another subgenus of lizard infecting Plasmodium.

HOST RANGE

Host range among the mammalian orders is non uniform. At least 29 species infect non human primates; rodents outside the tropical parts of Africa are rarely affected; a few species are known to infect bats, porcupines and squirrels; carnivores, insectivores and marsupials are not known to act as hosts. The listing of host species among the reptiles has rarely been attempted. Ayala in 1978 listed 156 published accounts on 54 valid species and subspecies between 1909 and 1975. The regional breakdown was Africa: 30 reports on 9 species; Australia, Asia & Oceania: 12 reports on 6 species and 2 subspecies; Americas: 116 reports on 37 species.

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