Plasmodium malariae

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Plasmodium malariae

Giemsa-stained micrograph of a
mature Plasmodium malariae
schizont
Scientific classification
Kingdom: Protista
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: P. malariae

Binomial name
Plasmodium malariae
Feletti & Grassi, 1889

Contents
[hide]
• 1 Introduction
• 2 Agent
• 3 Synonyms
• 4 History
• 5 Epidemiology
• 6 Transmission
• 7 Vector
• 8 Reservoir
• 9 Incubation Period
• 10 Morphology
• 11 Clinical Presentation in humans
• 12 Diagnostics
• 13 Biology
○ 13.1 Life cycle
  13.1.1 Human Infection
 13.1.2 Liver Stage
 13.1.3 Erythrocytic Cycle
 13.1.4 Mosquito Stage
 13.1.5 Sexual Stage
• 14 Laboratory considerations
• 15 Management and Therapy
• 16 Public health and Prevention Strategies/Vaccines
• 17 See also
• 18 References

[edit] Introduction
Plasmodium malariae is a parasitic protozoa that causes malaria in humans. It is closely related
to Plasmodium falciparum and Plasmodium vivax which are responsible for most malarial
infection. While found worldwide, it is a so-called "benign malaria" and is not nearly as
dangerous as that produced by P. falciparum or P. vivax. P. malariae causes fevers that recur at
approximately three-day intervals (a quartan fever), longer than the two-day (tertian) intervals of
the other malarial parasites.
[edit] Agent
Plasmodium malariae is a protozoan from the Eukaryota Aconodiasida taxa and class.
[edit] Synonyms
Quartan malaria

[edit] History
Plasmodium malaria has been recognized since the Greek and Roman civilizations over 2,000
years ago, with different patterns of fever described by the early Greeks[1]. In 1880, Alphonse
Laveran discovered that the causative agent for malaria is a parasite[2]. Detailed work of Golgi in
1886 demonstrated that in some patients there was a relationship between the 72-hour life cycle
of the parasite and the chill and fever patterns in the patient[3]. The same observation was found
for parasites with 48-hour cycles[4]. Golgi concluded that there must be more than one species of
malaria parasite responsible for these different patterns of infection[5].

[edit] Epidemiology
This year, approximately 500 million people will be infected with malaria worldwide[6]. Of those
infected, roughly two million will die from the disease[7]. Malaria is caused by four Plasmodium
species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium
malariae[8]. At any one time, an estimated 300 million people are said to be infected with at least
one of these Plasmodium species and so there is a great need for the development of effective
treatments for decreasing the yearly mortality and morbidity rates[9].

Arguably, P. malariae is the least studied of the four species that infect humans, in part because
of its low prevalence and milder clinical manifestations compared to the three other species. It is
widespread throughout sub-Saharan Africa, much of southeast Asia, Indonesia, on many of the
islands of the western Pacific and in areas of the Amazon Basin of South America[10]. In endemic
regions, prevalence ranges from less than 4% to more than 20%[11], but there is evidence that P.
malariae infections are vastly underreported.[12]
[edit] Transmission
P. malariae can be maintained at very low infection rates among a sparse and mobile population
because unlike the other Plasmodium parasites, it can remain in a human host for an extended
period of time and still remain infectious to mosquitoes[13].

[edit] Vector
The vector of transmission of the parasite is the female Anopheles mosquito and many different
species have been shown to transmit the parasite at least experimentally[14].Collins and Jeffrey
report over thirty different types of species, which vary by geographic region[15].

[edit] Reservoir
There are no animal reservoirs for P. malariae.
[edit] Incubation Period
Information about the prepatent period of P. malariae associated malaria is limited, but the data
suggests that there is great variation, often time depending on the strain of P. malariae parasite[16].
Usually, the prepatent period ranges from 16 to 59 days[17]

[edit] Morphology
The ring stages that are formed by the invasion of merozoites released by rupturing liver stage
schizonts are the first stages that appear in the blood[18]. The ring stages grow slowly but soon fill
one-fourth to one-third of the parasitized cell[19] Pigment increases rapidly and the half-grown
parasite may have from 30 to 50 jet-black granules[20]. The parasite changes various shapes as it
grows and stretches across the host cell to form the band form[21].

[edit] Clinical Presentation in humans

Plasmodium malariae causes a long-lasting, chronic infection that in some cases can last a
lifetime. The P. malariae parasite has several differences between it and the other Plasmodium
parasites. One being that maximum parasite counts are usually low compared to those in patients
infected with P. falciparum or P. vivax[22]. The reason for this can be accounted for by the lower
number of merozoites produced per erythrocytic cycle, the longer 72-hour developmental cycle
(compared to the 48-hour cycle of P. vivax and P. falciparum), the preference for development in
older erythrocytes and the resulting earlier development of immunity by the human host[23].
Another defining feature of P. malariae is that the fever manifestations of the parasite are more
moderate relative to those of P. falciparum and P. vivax and fevers show quartan periodicity[24].
Along with bouts of fever and more general clinical symptoms such as chills and nausea, the
presence of edema and the nephrotic syndrome has been documented with some P. malariae
infections[25]. It has been suggested that immune complexes may cause structural glomerular
damage and that renal disease may also occur[26]. Although P. malariae alone has a low morbidity
rate, it does contribute to the total morbidity caused by all Plasmodium species, as manifested in
the incidences of anemia, low birth rate and reduced resistance to other infections[27].
Due to a similarity in the appearances of the pathogens, P. knowlesi infections are often
misdiagnosed as P. malariae infections. Molecular analysis is usually required for an accurate
diagnosis [28].

[edit] Diagnostics
The preferable method for diagnosis of P. malariae is through the examination of peripheral
blood films stained with Giemsa stain[29]. PCR techniques are also commonly used for diagnoses
confirmation as well as to separate mixed Plasmodium infections[30]. Even with these techniques,
however, it may still be impossible to differentiate infections, as is the case in areas of South
America where humans and monkeys coexist and P. malariae and P. brasilianum are not easily
distinguishable[31].
[edit] Biology
[edit] Life cycle
P. malariae is the only human malaria parasite that causes fevers that recur at approximately
three-day intervals (therefore occurring evey fourth day, a quartan fever), longer than the two-
day (tertian) intervals of the other malarial parasites.[32]
[edit] Human Infection
[edit] Liver Stage
In this stage, many thousands of merozoites are produced in each schizont[33]. As the merozoites
are released, they invade erythrocytes and initiate the erythrocytic cycle, where the parasite
digests hemoglobin to obtain amino acids for protein synthesis[34].
[edit] Erythrocytic Cycle
The total length of the intraerythrocytic development is roughly 72 hours for P. malariae.[35]
At the schizont stage, after schizogonic division, there are roughly 6-8 parasite cells in the
erythrocyte.[35]
Following the erythrocytic cycle, which lasts for seventy two hours on average, six to fourteen
merozoites are released to reinvade other erythrocytes[36]. Finally, some of the merozoites
develop into either micro- or macrogametocytes[37]. The two types of gametocytes are taken into
the mosquito during feeding and the cycle is repeated[38]. There are no animal reservoirs for P.
malariae.
[edit] Mosquito Stage
Similar to the other human- infecting Plasmodium parasites, Plasmodium malariae has distinct
developmental cycles in the Anopheles mosquito and in the human host[39]. The mosquito serves
as the definitive host and the human host is the intermediate[40]. When the Anopheles mosquito
takes a blood meal from an infected individual, gametocytes are ingested from the infected
person[41]. A process known as exflagellation of the microgametocyte soon ensues and up to eight
mobile microgametes are formed[42].
[edit] Sexual Stage
Following fertilization of the macrogamete, a mobile ookinete is formed, which penetrates the
peritropic membrane surrounding the blood meal and travels to the outer wall of the mid-gut of
the mosquito[43]. The oocyst then develops under the basal membrane and after a period of two to
three weeks a variable amount of sporozoites are produced within each oocyst[44]. The number of
sporozoites that are produced varies with temperature and can range from anywhere between
many hundreds to a few thousand[45]. Eventually, the oocyst ruptures and the sporozoites are
released into the hemocoel of the mosquito3. The sporozoites are then carried by the circulation
of the hemolymph to the salivary glands, where they become concentrated in the acinal cells[46].
A small number of sporozoites are introduced into the salivary duct and injected into the venules
of the bitten human[47]. This initiates the cycle in the human liver[48].
[edit] Laboratory considerations
P. vivax and P. ovale that has been sitting in EDTA for more than half-an-hour before the blood
film is made will look very similar in appearance to P. malariae, which is an important reason to
warn the laboratory immediately when the blood sample is drawn so they can process the sample
as soon as it arrives.
Microscopically, the parasitised red blood cell (erythrocyte) is never enlarged and may even
appear smaller than that of normal red blood cells. The cytoplasm is not decolorized and no dots
are visible on the cell surface. The food vacuole is small and the parasite is compact. Cells
seldom host more than one parasite. Band forms, where the parasite forms a thick band across
the width of the infected cell, are characteristic of this species (and some would say is
diagnostic). Large grains of malarial pigment are often seen in these parasites: more so than any
other Plasmodium species. 8 merozoites

[edit] Management and Therapy

Failure to detect some P. malariae infections has lead to modifications of the species-specific
primers and to efforts towards the development of real-time PCR assays[49]. The development of
such an assay has included the use of generic primers that target a highly conserved region of the
18S rRNA genes of the four human-infecting species of Plasmodium[50]. This assay was found to
be highly specific and sensitive. Although serologic tests are not specific enough for diagnostic
purposes, they can be used as basic epidemiologic tools[51]. The immunofluorescent-antibody
(IFA) technique can be used to measure the presence of antibodies to P. malariae[52]. A pattern has
emerged in which an infection of short duration causes a rapidly declining immune response, but
upon re-infection or recrudescence, the IFA level rises significantly and remains present for
many months or years[53].
The increasing need to correctly identify P. malariae infection is underscored by its possible anti-
malarial resistance. In a study by Müller-Stöver et. al., the researchers presented three patients
who were found to be infected with the parasite after taking anti-malarial medications[54]. Given
the slower pre-erythrocytic development and longer incubation period compared to the other
malaria causing plasmodium species, the researchers hypothesized that the anti-malarials may
not be effective enough against the pre-erythrocytic stages of P. malariae[55]. They thought that
further development of P. malariae can occur when plasma concentrations of the anti-malarials
gradually decrease after the anti-malarial medications are taken. According to Dr. William E.
Collins from the Center of Disease Control (CDC), chloroquine is most commonly used for
treatment and no evidence of resistance to this drug has been found[56]. In that event, it is possible
that the results from Müller-Stöver et. al provided isolated incidences.

[edit] Public health and Prevention Strategies/Vaccines

The food vacuole is the specialized compartment that degrades hemoglobin during the asexual
erythrocytic stage of the parasite[57]. It is implied that effective drug treatments can be developed
by targeting the proteolytic enzymes of the food vacuole. In a paper published in 1997, Westling
et. al[58] focused their attention on the aspartic endopeptidase class of enzymes, simply called
plasmepsins. They sought to characterize the specificity for the enzymes cloned from P. vivax
and P. malariae. Using substrate specificity studies and inhibitor analysis, it was found that the
plasmepsins for P. malariae and P. vivax showed less specificity than that for P. falciparum.
Unfortunately, this means that the development of a selective inhibitor for P. malariae may prove
more challenging than the development of one for P. falciparum[59]. Another study by Bruce et.
al[60] presented evidence that there may be regular genetic exchange within P. malariae
populations. Six polymorphic genetic markers from P. malariae were isolated and analyzed in 70
samples of naturally acquired P. malariae infections from different parts of the world. The data
showed a high level of multi-genotypic carriage in humans[61].

Both of these experiments illustrate that development of vaccine options will prove challenging,
if not impossible. Dr. William Collins doubts that anyone is currently looking for possible
vaccines for P. malariae[62] and given the complexity of the parasite it can be inferred why. He
states that very few studies are conducted with this parasite[63], perhaps as a result of its perceived
low morbidity and prevalence. Collins sights the great restrictions of studies with chimpanzees
and monkeys as a sizeable barrier[64]. Since the Plasmodium brasilianium parasite that infects
South American monkeys is thought to be an adapted form of P. malariae, more research with P.
brasilianium may hold valuable insight into P. malariae.
The continuing work with the plasmepsin associated with P. malariae, plasmepsin 4, by Professor
Ben Dunn and his research team from the University of Florida may provide hope for long term
malaria control in the near future[65].