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microgametocyte

Plasmodium

[plaz-moh-dee-uhm]

A plasmodium is also the macroscopic form of the protist known as a slime mould.

Plasmodium is a genus of parasitic protozoa. Infection with this genus is known as malaria. The genus Plasmodium was created in 1885 by Marchiafava and Celli. Currently over 200 species in this genus are recognized and new species continue to be described.

Of the 200+ known species of Plasmodium, at least 10 species infect humans. Other species infect animals, including birds, reptiles and rodents. The parasite always has two hosts in its life cycle: a mosquito vector and a vertebrate host.

The genus is currently (2006) in need of reorganization as it has been shown that parasites belonging to the genera Haemocystis and Hepatocystis appear to be closely related to Plasmodium. It is likely that other species such as Haemoproteus meleagridis will be included in this genus once it is revised.

History

The organism itself was first seen by Laveran on November 6th 1880 at a military hospital in Constantine, Algeria, when he discovered a microgametocyte exflagellating. Manson (in 1894) hypothesised that mosquitoes could transmit malaria - an association made considerably earlier in India, possibly as early as 2000BC. This hypothesis was experimentally confirmed independently by the Italian professor Giovanni Battista Grassi and the British physician Ronald Ross both in 1898. Ross demonstrated the existence of Plasmodium in the wall of the midgut and salivary glands of a Culex mosquito. 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.

Grassi also proposed in 1900 the existence of an exerythrocytic stage in the life cycle: this was later confirmed by Short, Garnham, Covell and Shute (in 1948) who found Plasmodium vivax in the human liver.

Life cycle

Mosquitoes of the genera Culex, Anopheles, Culiceta, Mansonia and Aedes may act as vectors. The currently known vectors for human malaria (> 10 species) all belong to the genus Anopheles. Bird malaria is commonly carried by species belonging to the genus Culex. Only female mosquitoes bite. Aside from blood both sexes live on nectar, but one or more blood meals are needed by the female for egg laying as the protein content of nectar is very low. The life cycle of Plasmodium was discovered by Ross who worked with species from the genus Culex.

The life cycle of Plasmodium is very complex. Sporozoites from the saliva of a biting female mosquito are transmitted to either the blood or the lymphatic system of the recipient. The sporozoites then migrate to the liver and invade hepatocytes. This latent or dormant stage of the Plasmodium sporozoite in the liver is called the hypnozoite.

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 have been subsequently shown to lodge in the pulmonary capilaries and to slowly disintergrate there over 48-72 hours releasing merozoites. Erythrocyte invasion is enhanced when blood flow is slow and the cells are tightly packed: both of these conditions are found in the alveolar capilaries.

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 generalisations may be premature at this time.

At the molecular level a set of enzymes known as plasmepsins which are aspartic acid proteases are used to degrade hemoglobin.

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.

In the mosquito's midgut, the gametocytes develop into gametes and fertilize each other, forming motile zygotes called ookinetes. The ookinetes penetrate and escape the midgut, then embed themselves onto the exterior of the gut membrane. Here they divide many times to produce large numbers 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 majority 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. The sporozoites which successfully enter the blood stream move to the liver where they begin the cycle again.

The pattern of alternation of sexual and asexual reproduction which may seem confusing at first is a very common pattern in parasitic species. The evolutionary advantages of this type of life cycle were recognised by Mendel.

Under favourable conditions asexual reproduction is superior to sexual as the parent is well adapted to its environment and its descendents share these genes. Transferring to a new host or in times of stress, sexual reproduction is generally superior as this produces a shuffling of genes which on average at a population level will produce individuals better adapted to the new environment.

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 malariae, Plasmodium ovale and Plasmodium vivax hypnozoites have been shown to occur. Reactivation does not occur in infections with Plasmodium falciparum. It is not known if hypnozoite reactivaction may occur with any of the remaining species that infect humans but this is presumed to be the case.

A single report of recurrence of P. falciparum in a patient with sickle cell anaemia exists but this needs additional confirmation as liver forms are not known to occur in P. falciparum infections.

Evolution

The life cycle is probably best understood in terms of its evolution. At the present time (2007) DNA sequences are available from fewer 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 data becomes available.

The Apicomplexa — the phylum to which Plasmodium belongs - are thought to have originated within the Dinoflagellates — a large group of photosynthetic protozoa. It is thought that the ancestors of the Apicomplexa were originally prey organisms that evolved the ability to invade the intestinal cells and subsequently lost their photosynthetic ability. Many of the species within the Apicomplexia still possess a plastid (the organelle in which photosynthesis occurs in eukaryotes): some that do not have evidence of plastid genes within their genome. These plastids - unlike those found in algae - are not photosynthetic. Its function is not known but there is some suggestive evidence that it may be involved in reproduction.

Some extant dinoflagelates, however, can invade the bodies of jellyfish and continue to photosynthesize, which is possible because jellyfish bodies are almost transparent. In other organisms with opaque bodies this ability would most likely rapidly be lost. The recent (2008) description of a photosynthetic protist related to the Apicomplexia with a functional plastid supports this hypothesis.

Current (2007) theory suggests that the genera Plasmodium, Hepatocystis and Haemoproteus evolved from one or more Leukocytozoon species. Parasites of the genus Leukocytozoan infect white blood cells (leukocytes), 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 Leukocytozoon 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.

Leukocytes, hepatocytes and most spleen cells actively phagocytose particulate matter making entry into the cell easier for the parasite. The mechanism of entry of Plasmodium species into erythrocytes is still very unclear taking as it does 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 Leukocytozoon 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 genomic 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.

Mosquitoes evolved in what is now South America about 230 million years ago. There are over 3500 species recognised 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.

Presently it seems probable that birds were the first group infected by Plasmodium followed by the reptiles—probably the lizards. At some point primates and rodents became infected. The remaining species infected outside these groups seem likely to be due to relatively recent events.

Genome

All Plasmodium species examined to date have 14 chromosomes, one mitochondrion and one plastid. The chromosomes whose length is known vary from 500 kilobases to 3.5 megabases in length. It is presumed that this is the pattern throughout the genus. The typical chormosome number of Leukcytozoon has not yet been established.

The genome of four Plasmodium species have been sequenced. These species are Plasmodium falciparum, Plasmodium knowlesi, Plasmodium vivax and Plasmodium yoelli. All these species have 14 chromosomes and genomes of about 25 megabases results consistent with earlier estimates.

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

Family Garniidae

Family Leucocytozoidae

Family Plasmodiidae

  • Genus Billbraya
  • Genus Dionisia
  • Genus Hepatocystis
  • Genus Mesnilium
  • Genus Nycteria
  • Genus Plasmodium
    • Subgenus Asiamoeba
    • Subgenus Bennettinia
    • Subgenus Carinamoeba
    • Subgenus Giovannolaia
    • Subgenus Haemamoeba
    • Subgenus Huffia
    • Subgenus Lacertaemoba
    • Subgenus Laverania
    • Subgenus Novyella
    • Subgenus Plasmodium
    • Subgenus Paraplasmodium
    • Subgenus Sauramoeba
    • Subgenus Vinckeia
  • Genus Polychromophilus
  • Genus Rayella
  • Genus Saurocytozoon

Diagnostic characteristics of the genus Plasmodium

  • Forms gamonts in erythrocytes
  • Merogony occurs in erythrocytes and in other tissues
  • Hemozoin is present
  • Vectors are either mosquitos or sandflies
  • Vertebrate hosts include mammals, birds and reptiles

Notes:

The genera Plasmodium, Fallisia and Saurocytozoon all cause malaria in lizards. All are carried by Diptera (flies). Pigment is absent in the Garnia. Non pigmented gametocytes are typically the only forms found in Saurocytozoon: pigmented forms may be found in the leukocytes occasionally. Fallisia produce non pigmented asexual and gametocyte forms in leukocytes and thrombocytes.

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 elongatum (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 there 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 Leukocytozoon

Subgenera: discussion

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.

The only two species in the sub genus Laverania are P. falciparum and P. reichenowi. 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 is no longer thought to be the case.

Species infecting monkeys and apes (the higher primates) with the exceptions of P. falciparum and P. reichenowi are classified in the subgenus Plasmodium. 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.

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 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.

Unlike the mammalian and bird malarias those affecting 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.

Classification criteria for subgenera

Avian species

Species in the subgenus Bennettinia have the following characteristics:

  • Schizonts contain scant cytoplasm, are often round, do not exceed the size of the host nucleus and stick to it.
  • Gametocytes while varying in shape tend to be round or oval, do not exceed the size of the nucleus and stick to it.

Species in the subgenus Giovannolaia have the following characteristics:

  • Schizonts contain plentiful cytoplasm, are larger than the host cell nucleus and frequently displace it. They are found only in mature erythrocytes.
  • Gametocytes are elongated.
  • Exoerythrocytic schizogony occurs in the mononuclear phagocyte system.

Species in the subgenus Haemamoeba have the following characteristics:

  • Mature schizonts are larger than the host cell nucleus and commonly displace it.
  • Gametocytes are large, round, oval or irregular in shape and are substantially larger than the host nucleus.

Species in the subgenus Huffia have the following characteristics:

  • Mature schizonts, while varying in shape and size, contain plentiful cytoplasm and are commonly found in immature erthryocytes.
  • Gametocytes are elongated.

Species in the subgenus Novyella have the following characteristics:

  • Mature schisonts are either smaller than or only slightly larger than the host nucleus. They contain scanty cytoplasm.
  • Gametocytes are elongated. Sexual stages in this subgenus resemble those of Haemoproteus.
  • Exoerythrocytic schizogony occurs in the mononuclear phagocyte system

Reptile species

Species in the subgenus Carinamoeba have the following characteristics:

  • Infect lizards
  • Schizonts normally give rise to less than 8 merozoites

Species in the subgenus Sauramoeba have the following characteristics:

  • Infect lizards
  • Schizonts normally give rise to more than 8 merozoites

Notes

  • The erythrocytes of both reptiles and birds retain their nucleus, unlike those of mammals. The reason for the loss of the nucleus in mammalian erythocytes remains unknown.

Species listed by subgenera

Plasmodium (Asiamoeba) draconis
Plasmodium (Asiamoeba) vastator

Plasmodium (Bennettinia) juxtanucleare

Plasmodium (Carinamoeba) basilisci
Plasmodium (Carinamoeba) clelandi
Plasmodium (Carinamoeba) lygosomae
Plasmodium (Carinamoeba) mabuiae
Plasmodium (Carinamoeba) minasense
Plasmodium (Carinamoeba) rhadinurum
Plasmodium (Carinamoeba) volans

Plasmodium (Giovannolaia) anasum
Plasmodium (Giovannolaia) circumflexum
Plasmodium (Giovannolaia) dissanaikei
Plasmodium (Giovannolaia) durae
Plasmodium (Giovannolaia) fallax
Plasmodium (Giovannolaia) formosanum
Plasmodium (Giovannolaia) gabaldoni
Plasmodium (Giovannolaia) garnhami

Plasmodium (Giovannolaia) gundersi
Plasmodium (Giovannolaia) hegneri
Plasmodium (Giovannolaia) lophurae
Plasmodium (Giovannolaia) pedioecetii
Plasmodium (Giovannolaia) pinnotti
Plasmodium (Giovannolaia) polare

Plasmodium (Haemamoeba) cathemerium
Plasmodium (Haemamoeba) coggeshalli
Plasmodium (Haemamoeba) coturnixi
Plasmodium (Haemamoeba) elongatum
Plasmodium (Haemamoeba) gallinaceum
Plasmodium (Haemamoeba) giovannolai
Plasmodium (Haemamoeba) lutzi
Plasmodium (Haemamoeba) matutinum
Plasmodium (Haemamoeba) paddae
Plasmodium (Haemamoeba) parvulum
Plasmodium (Haemamoeba) relictum
Plasmodium (Haemamoeba) tejera

Plasmodium (Huffia) elongatum
Plasmodium (Huffia) hermani

Plasmodium (Lacertaemoba) floridense
Plasmodium (Lacertaemoba) tropiduri

Plasmodium (Laverania) falciparum
Plasmodium (Laverania) reichenowi

Plasmodium (Novyella) ashfordi
Plasmodium (Novyella) bertii
Plasmodium (Novyella) bambusicolai
Plasmodium (Novyella) columbae
Plasmodium (Novyella) corradettii
Plasmodium (Novyella) dissanaikei
Plasmodium (Novyella) globularis
Plasmodium (Novyella) hexamerium
Plasmodium (Novyella) jiangi
Plasmodium (Novyella) kempi
''Plasmodium (Novyella) megaglobularis
Plasmodium (Novyella) nucleophilum
Plasmodium (Novyella) papernai
Plasmodium (Novyella) paranucleophilum
Plasmodium (Novyella) rouxi
Plasmodium (Novyella) vaughani

Plasmodium (Paraplasmodium) chiricahuae
Plasmodium (Paraplasmodium) mexicanum
Plasmodium (Paraplasmodium) pifanoi

Plasmodium (Plasmodium) bouillize
Plasmodium (Plasmodium) brasilianum
Plasmodium (Plasmodium) cercopitheci
Plasmodium (Plasmodium) coatneyi
Plasmodium (Plasmodium) cynomolgi
Plasmodium (Plasmodium) eylesi
Plasmodium (Plasmodium) fieldi
Plasmodium (Plasmodium) fragile
Plasmodium (Plasmodium) georgesi
Plasmodium (Plasmodium) girardi
Plasmodium (Plasmodium) gonderi
Plasmodium (Plasmodium) inui
Plasmodium (Plasmodium) jefferyi
Plasmodium (Plasmodium) joyeuxi
Plasmodium (Plasmodium) knowlei
Plasmodium (Plasmodium) hyobati
Plasmodium (Plasmodium) malariae
Plasmodium (Plasmodium) ovale
Plasmodium (Plasmodium) petersi
Plasmodium (Plasmodium) pitheci
Plasmodium (Plasmodium) rhodiani
Plasmodium (Plasmodium) schweitzi
Plasmodium (Plasmodium) semiovale
Plasmodium (Plasmodium) semnopitheci
Plasmodium (Plasmodium) silvaticum
Plasmodium (Plasmodium) simium
Plasmodium (Plasmodium) vivax
Plasmodium (Plasmodium) youngi

Plasmodium (Sauramoeba) achiotense
Plasmodium (Sauramoeba) adunyinkai
Plasmodium (Sauramoeba) aeuminatum
Plasmodium (Sauramoeba) agamae
Plasmodium (Sauramoeba) beltrani
Plasmodium (Sauramoeba) brumpti
Plasmodium (Sauramoeba) cnemidophori
Plasmodium (Sauramoeba) diploglossi
Plasmodium (Sauramoeba) giganteum
Plasmodium (Sauramoeba) heischi
Plasmodium (Sauramoeba) josephinae
Plasmodium (Sauramoeba) pelaezi
Plasmodium (Sauramoeba) zonuriae

Plasmodium (Vinckeia) achromaticum
Plasmodium (Vinckeia) aegyptensis
Plasmodium (Vinckeia) anomaluri
Plasmodium (Vinckeia) atheruri
Plasmodium (Vinckeia) berghei
Plasmodium (Vinckeia) booliati
Plasmodium (Vinckeia) brodeni
Plasmodium (Vinckeia) bubalis
Plasmodium (Vinckeia) bucki
Plasmodium (Vinckeia) caprae
Plasmodium (Vinckeia) cephalophi
Plasmodium (Vinckeia) chabaudi
Plasmodium (Vinckeia) coulangesi
Plasmodium (Vinckeia) cyclopsi
Plasmodium (Vinckeia) foleyi
Plasmodium (Vinckeia) girardi
Plasmodium (Vinckeia) inopinatum
Plasmodium (Vinckeia) lemuris
Plasmodium (Vinckeia) melanipherum
Plasmodium (Vinckeia) odocoilei
Plasmodium (Vinckeia) percygarnhami
Plasmodium (Vinckeia) sandoshami
Plasmodium (Vinckeia) traguli
Plasmodium (Vinckeia) tyrio
Plasmodium (Vinckeia) uilenbergi
Plasmodium (Vinckeia) vinckei
Plasmodium (Vinckeia) watteni
Plasmodium (Vinckeia) yoelli

Notes

Ophidiella was a subgenus created by Garnham in 1966 for the species infecting snakes. Presently (2007) it is no longer in use.

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.

Because of the number of species parasited by Plasmodium further discussion has been broken down into following pages:

Species reclassified into other genera

The literature is replete with species initially classified as Plasmodium that have been subsequently reclassified. With DNA taxonomy some of these may be once again be classified as Plasmodium. Some of these species are listed here for completeness.

The following species are currently (2007) regarded as belonging to the genus Hepatocystis rather than Plasmodium:

  • Plasmodium epomophori
  • Plasmodium kochi
  • Plasmodium limnotragi Van Denberghe 1937
  • Plasmodium pteropi Breinl 1911
  • Plasmodium ratufae Donavan 1920
  • Plasmodium vassali Laveran 1905

The following species are now considered to belong to the genus Haemoemba rather than to Plasmodium:

  • Plasmodium praecox
  • Plasmodium rousseleti

The following species been reclassified as a species of Garnia:

  • Plasmodium gonatodi

Host note: Hepatocystis epomophori infects the bat (Hypsignathus monstruosus)

Species of dubious validity

The following species are currently regarded as questionable validity (nomen dubium)

References

Further reading

Standard reference books for the identification of Plasmodium species

  • Laird, Marshall (1998). Avian Malaria in the Asian Tropical Subregion. Santa Clara, CA: Springer-Verlag TELOS.
  • Garnham PCC (1966). Malaria Parasites and Other Haemosporidia. Oxford: Blackwell Science Ltd.

This book remains the standard reference work on malarial species classification.

External links

Some history of malaria - http://muse.jhu.edu/journals/bulletin_of_the_history_of_medicine/v079/79.2slater.html

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