Plasmodium
From Wikipedia, the free
encyclopedia
This article is
about the malaria parasite. For the stage in the life-cycle of some organisms,
see plasmodium (life cycle).
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Plasmodium is a genus of Apicomplexan parasites. Infection by these organisms is
known as malaria.
The genus Plasmodium
was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently
over 200 species of this genus are recognized and new species continue to be
described.
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.[citation needed]
Biology
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 on the Plasmodium falciparum biology page.
Diagnostic characteristics of the genus Plasmodium
- 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.[3]
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.[4]
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.[5]
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.[6][7]
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,[8]
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[9]
and Plasmodium vivax,[10]
but not in Plasmodium malariae,[11][12]
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.[13]
These merosomes lodge in the pulmonary capillaries and slowly disintegrate
there over 48–72 hours releasing merozoites.[14]
The membrane of the merosome is derived from the host hepatocyte.[15] 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[16]
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.[17]
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.[18]
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.[19]
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.[20]
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[21]
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.[22]
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.[23]
The ratio of asexual to sexual forms is between 10:1 and 156:1[24][25]
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.[26]
Gametocyte
carriage is associated with anaemia.[27]
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.[28]
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.[29] 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.[30]
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.[31]
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.[32]
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 and fertilize
each other, forming motile zygotes called ookinetes. It has been shown that
up to 50% of the ookinetes may undergo apoptosis within the midgut.[33][34]
The reason for this behavior is unknown. While in the mosquito gut the
parasites form thin cytoplasmic extensions to communicate with each other.[35]
These structures persist from the time of gametocyte activation until the
zygote transforms into an ookinete. The function of these tubular structres
remains to be discovered.
The ookinetes
penetrate and escape the midgut, then embed themselves onto the exterior of the
gut membrane. As in the liver the parasite tends to invade a number of cells
before choosing one to reside in. The reason for the behavior is not known.
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 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.[36]
The escape of
the gametocytes from the erythrocytes has been until recently obscure.[37]
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 vacoule 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.
Infection of
the mosquito has noticeable effects on the host. The presence of the parasite
induces apotosis of the egg follicles.[38]
The development
of the parasite in the mosquito is temperature dependent with higher
temperatures being associated with more rapid development.[39]
Higher temperatures appear to enhance the mosquito's immune system leading to a
lower average infection rate.
Discussion
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 Gregor
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.
The advantages
to asexual reproduction within a host can be seen from this simple model taken
from Cook.[40]
The proportion of hosts that are parasitised is assumed to be small. This being
the case the Poisson distribution is a reasonable model. If
the parasite is self fertilizing then the chance of successful reproduction is
1 - e-m where m is the proportion of the population parasitised. If
the parasite is a faculative bisexual one - one that requires the presence of
another parasite on the same host the likelihood of success is 1 - (1 + m)e-m.
If the parasite has two distinct sexes and requires both for reproduction, then
the chance of success is ∑ (1 - 21-n)(mn / n! e-m)
where the sum is taken between n = 2 and infinity. If m = 0.1 then the chance
of success of the self fertilizing parasite is 40 times that of one with
distinct sexes. The chance of success of the bisexual parasite is twice that of
the parasite with distinct sexes. For smaller values of m, the advantages of
self fertilization are even greater.
Given that this
parasite spends part of its life cycle in two different hosts it must use a
proportion of its available resources within each host. The proportion utilized
is currently unknown. Empirical estimates of this parameter are desirable for
modeling of its life cycle.
Dormant forms
Plasmodium falciparum malaria
A report of P.
falciparum malaria in a patient with sickle cell
anemia four years after exposure to the parasite has been published.[41]
A second report that P. falciparum malaria had become symptomatic eight
years after leaving an endemic area has also been published.[42]
A third case of
an apparent recurrence nine years after leaving an endemic area of P.
falciparum malaria has now been reported.[43]
A fourth case of recurrence in a patient with lung cancer has been reported.[44]
Two cases in pregnant women both from Africa but who had not lived there for
over a year have been reported.[45]
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.[46]
A second case of congenital malaria in twins due to P. falciparum has
been reported.[47]
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.[48]
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.
Plasmodium malariae
This parasite
is not thought to have a latent form but relapses have been reported.[49]
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.[50]
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.[51]
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.[52]
Similar merophores were found in the polymorph leukocytes and macrophages of
other murine malaria parasite, P.
yoelii nigeriensis[52]
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.[52]
on the presence of malaria parasites inside lymphatics suggest a mechanism for
the recrudescence and chronicity of malaria infection.[53]
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.[54]
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[55][56]
A recently identified apicomplexan found in Australian corals - Chromera
velia - has retained a photosynthetic plastid.[57]
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.[58]
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.[59]
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
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.[60]
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.[61]
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.[62]
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.[citation needed] It seems
likely that many of these species will be re-assigned after these studies have
been completed.[63][64]
For this reason the entire order is outlined here.
- Genus Fallisia
Lainson, Landau & Shaw 1974
Phylogenetic trees
- 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.
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[65]
- 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.[66]
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.[67]
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.[65]
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.[68]
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.[69]
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.
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.[70]
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.[71]
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[72]
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.[73]
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.[74]
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.[75]
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.[76]
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.[77]
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:[78]
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.[79]
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.
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.[78][82] 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.[74]
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.
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.[83]
A fifth—Bennettinia—was created in 1997 by Valkiunas.[84]
The relationships between the subgenera are the matter of current
investigation. Martinsen et al. 's recent (2006) paper outlines what is
currently (2007) known.[85]
The subgenera Haemamoeba, Huffia, and Bennettinia appear
to be monphylitic. Novyella appears to be well defined with occasional
exceptions. The subgenus Giovannolaia needs revision.[86]
P.
juxtanucleare is currently
(2007) the only known member of the subgenus Bennettinia.
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.[87]
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.[88]
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.
Classification criteria for subgenera
Bird infecting species
There are ~40
recognised bird species. Although over 50 species have been described, several
have been rejected as being invalid.
With the
exception of P. elongatum the exoerythrocytic stages occur in the
endothelial cells and those of the macrophage-lymphoid system. The exoerythrocytic
stages of P. elongatum parasitise the blood forming cells.
The various
subgenera are first distinguished on the basis of the morphology of the mature
gametocytes. Those of subgenus Haemamoeba are round or oval while those
of the subgenera Giovannolaia, Huffia and Novyella are
elongated. These latter genera are distinguished on the basis of the size of
the schizonts: Giovannolaia and Huffia have large schizonts while
those of Novyella are small.
Species in the
subgenus Bennettinia have the following characteristics:
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
schizonts 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 infecting species
All species in
these subgenera infect lizards.
Species in the
subgenus Asiamoeba have the following characteristics:
Species in the
subgenus Carinamoeba have the following characteristics:
- Schizonts
normally give rise to less than 8 merozoites
- Schizonts
are normally smaller than the host nucleus
Species in the
subgenus Fallisia have the following characteristics:
- Non-pigmented
asexual and gametocyte forms are found in leukocytes and thrombocytes
Species in the
subgenus Garnia have the following characteristics:
Species in the
subgenus Lacertaemoba have the following characteristics:
Species in the
subgenus Paraplasmodium have the following characteristics:
Species in the
subgenus Sauramoeba have the following characteristics:
- Schizonts
normally give rise to more than 8 merozoites
- Schizonts
are normally larger than the host nucleus
- Non-pigmented
gametocytes are typically the only forms found
- Pigmented
forms may be found in the leukocytes occasionally
All species in Ophidiella
infect snakes
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
Asiamoeba
Bennetinia
Carinamoeba
Giovannolaia
Haemamoeba
Huffia
Lacertamoeba
Laverania
Ophidiella
Novyella
Nyssorhynchus
Paraplasmodium
Plasmodium
Sauramoeba
Vinckeia
Host range
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.[89]
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 following
species have been assigned to the genus Plasmodium in the past:
Species of dubious validity
The following
species are currently regarded as questionable validity (nomen dubium).
See also
