Brief Summary

Plasmodium falciparum is one of the two protozoan parasites responsible for most of the world's cases of human malaria (the other being P. vivax). Hay et al. (2010) estimated that in 2010 there were around 450 million clinical cases of P. falciparum malaria in the world. Based on where they live, an estimated 2.5 billion people were at possible risk of infection with P. falciparum as of 2005. Three quarters of people exposed to P. falciparum risk live in just ten countries. (Guerra et al. 2006). According to Hay et al. (2010), around half the world’s estimated P. falciparum clinical cases (and nearly half the statistical uncertainty in estimates) derive from just four countries: India, Nigeria, Democratic Republic of the Congo (DRC), and Myanmar (Burma). 60% of the estimated world falciparum malaria burden falls in Africa and nearly a quarter on Nigeria and DRC alone. The current falciparum malaria burden in India is very unclear, but official surveillance numbers appear to be dramatic understimates. India's malaria problem is probably exacerbated by the unique problem of urban malaria, maintained by Anopheles stephensi. (Hay et al. 2010) Plasmodium falciparum is responsible for most of the nearly one million people (many of them children) killed by malaria each year.

Hedrick (2011) reviewed the population genetics of malaria resistance in humans. Hill (2011) reviewed efforts to develop a malaria vaccine from the vantage point of 2011.

In contrast to P. vivax, P. falciparum does not have a dormant liver stage. Instead, the gametocytes of P. falciparum can survive in the blood for months. (Mueller et al. 2007)

The human malaria parasite life cycle involves two hosts, a mosquito and a human. The life cycle is very complex, including both sexual and asexual phases (see life cycle diagram) and involves a stage in the liver as well as the blood stage, the latter being responsible for the clinical manifestations of the disease. (Centers for Disease Control Parasites and Health website)

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Common symptoms of malaria include:
  • fever
  • shivering
  • joint pain
  • vomiting
  • anaemia
  • convulsions
Severe malaria caused by P. falciparum can progress extremely quickly and lead to:
  • severe brain damage
  • cognitive impairments - especially in children
  • enlarged liver and/or spleen
  • severe headache
  • cerebral ischemia (lack of adequate blood flow)
  • low blood sugar
  • renal failure
  • coma
  • death - young children and pregnant women are especially vulnerable
Museum scientists are running a project in Uganda, aiming to:
  • better understand disease distribution in rural villages better
  • promote the distribution of bed-nets and treatment availability
  • understand the relationship between malaria and other tropical diseases
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Comprehensive Description


In the human:
  • during a blood meal, a malaria-infected female Anopheles mosquito injects P. falciparum parasites into the human host
  • the parasites travel via the blood to the liver, where they infect liver cells
  • they mature and move back to the blood where they undergo asexual multiplication inside the human red blood cells (ring-stage)
  • in the blood, some parasites can differentiate into sexual stages (gametocytes)
  • blood stage parasites are responsible for the symptoms of the disease
In the mosquito:
  • the gametocytes, male and female, are ingested by an Anopheles mosquito during a blood meal
  • while in the mosquito's stomach, the male parasite penetrates the female parasite and this new parasite form becomes motile, able to invade the midgut wall of the mosquito where it develops into oocysts (or eggs)
  • they grow, rupture, and release further parasites in a new form capable of moving towards the mosquito's salivary glands ready for inoculation into a new human host to perpetuate the malaria life cycle
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Physical Description

Look Alikes


The most obvious features that distinguish Plasmodium vivax from P. falciparum include the development of dormant forms in the liver known as "hypnozoites", which cause subsequent infections in the blood called relapses; the appearance (sometimes before onset of clinical symptoms) of round gametocytes in the peripheral blood (i.e., not banana-shaped gametocytes like those produced by P. falciparum); a predilection (or requirement) of merozoites for reticulocytes as host cells; circulation of all blood-stage developmental forms in the peripheral blood; the absence of electron-dense protrusions (known as knobs in P. falciparum); and the presence of numerous caveolae–vesicle complexes along the surface of infected red blood cells. (Mueller et al. 2009 and references therein)

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Diseases and Parasites


Malaria diagnosis
P. falciparum can be identified using several methods which are used to diagnose malaria disease.

Microscopic examination of blood films
The most economic, preferred and reliable diagnostic method for malaria is microscopic examination of blood films. Thin or thick films stained with Giemsa allow a skilled microscope technician to identify parasites and have an idea of infection intensity - or parasitaemia.New microscopy methods are being developed, with different staining techniques, for example a portable fluorescent microscope allows for a quicker but less reliable diagnosis. Fluorescence is incredibly useful for rapid identification of parasites, featured as bright green fluorescence in a black background.

Antigen tests
For faster diagnosis when microscopy is not available or laboratory staff are not experienced, there are now commercial antigen detection tests that require only a drop of blood. Malaria rapid diagnostic tests (RDTs) take 15–20 minutes to make a diagnosis. Unlike microscopy-based diagnosis, RDTs tend to be more expensive and harder to make available in rural areas.

Molecular methods
Molecular methods are available in some clinical laboratories. Based on the polymerase chain reaction (PCR), they are more accurate than microscopy. However, these methods are expensive and require a specialised laboratory.

Malaria treatments
Active malaria infection with P. falciparum requires hospitalisation so pathology can be minimised and parasitaemia contained using specific antimalarial drugs.
P. falciparum is able to develop resistance to most anti-malarial drugs, and for this reason the World Health Organisation now recommends the use of two or more drugs simultaneously. The latest most effective drugs are artemisinin combination therapies (ACTs). The primary compound - artemisinin - is combined with several others, such as mefloquine (ASMQ), lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin) and antifolates (Ariplus).
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General Ecology

Distribution ecology

Global levels of malaria have not been mapped since the 1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project to rectify this. Malaria is endemic in the tropics, from South America, Sub-Saharan Africa - where it is most deadly - to Southeast Asia, affecting the lives of millions of people worldwide.
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Evolution and Systematics


Systematics and Taxonomy

There are more than 150 named species of Plasmodium that infect various species of vertebrates. Four species are well known as true parasites of humans, utilizing humans almost exclusively as a natural intermediate host: P. falciparum, P. vivax, P. ovale and P. malariae. In recent years it has become apparent that the simian malaria parasite P. knowlesi also regularly infects humans, as well as its natural monkey intermediate hosts. (Centers for Disease Control Parasites and Health website) Furthermore, it is now apparent that there are likely two distinct Plasmodium species that have both been referred to as P. ovale (Sutherland et al. 2010; Oguike et al. 2011).

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Plasmodium falciparum

Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species (also called malignant[2] or falciparum[3] malaria) is the most dangerous form of malaria,[4] with the highest rates of complications and mortality. As of the latest World Health Organization report in 2014, there were 198 million cases of malaria worldwide in 2013, with an estimated death of 584,000.[5][6] It is much more prevalent in sub-Saharan Africa than in many other regions of the world; in most African countries, over 75% of cases were due to P. falciparum, whereas in most other countries with malaria transmission, other, less virulent plasmodial species predominate. Almost every malarial death is caused by P. falciparum.[7]


Malaria is caused by an infection with protozoa of the genus Plasmodium. The name malaria, from the Italian mala aria, meaning "bad air", comes from the linkage suggested by Giovanni Maria Lancisi (1717) of malaria with the poisonous vapours of swamps. This species name comes from the Latin falx, meaning "sickle", and parere meaning "to give birth". 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. Patrick Manson (1894) hypothesised that mosquitoes could transmit malaria. This hypothesis was experimentally confirmed independently by Giovanni Battista Grassi and Ronald Ross in 1898. Grassi (1900) proposed an exerythrocytic stage in the lifecycle, later confirmed by Short, Garnham, Covell, and Shute (1948), who found Plasmodium vivax in the human liver.

Around the world, malaria is the most significant parasitic disease of humans, and claims the lives of more children worldwide than any other infectious disease. Since 1900, the area of the world exposed to malaria has been halved, yet two billion more people are presently exposed. Morbidity, as well as mortality, is substantial. Infection rates in children in endemic areas are on the order of 50%. Chronic infection has been shown to reduce school scores by up to 15%. Reduction in the incidence of malaria coincides with increased economic output.[8]

While no effective vaccines are known for any of the six or more species that cause human malaria, drugs have been employed for centuries. In 1640, Huan del Vego first employed the tincture of the cinchona bark for treating malaria; the native Indians of Peru and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "Jesuits' bark" to England. Its first recorded use there was by Dr John Metford of Northampton in 1656. Morton (1696) presented the first detailed description of the clinical picture of malaria and of its treatment with cinchona. Gize (1816) studied the extraction of crystalline quinine from the cinchona bark, and Pelletier and Caventou (1820) in France extracted pure quinine alkaloids, which they named quinine and cinchonine.

Plasmodium life cycle[edit]

Seasonal temperature suitability for transmission of P. falciparum. The Z(T) normalized index of temperature suitability for P. falciparum displayed by week across an average year.

The lifecycle of all Plasmodium species is complex. Infection in humans begins with the bite of an infected female Anopheles mosquito. Sporozoites released from the salivary glands of the mosquito enter the bloodstream during feeding, quickly invading liver cells (hepatocytes). Sporozoites are cleared from the circulation within 30 minutes. During the next 14 days in the case of P. falciparum, the liver-stage parasites differentiate and undergo asexual multiplication, resulting in tens of thousands of merozoites that burst from the hepatocyte. Individual merozoites invade red blood cells (erythrocytes) and undergo an additional round of multiplication, producing 12-16 merozoites within a schizont. The length of this erythrocytic stage of the parasite lifecycle depends on the parasite species: an irregular cycle for P. falciparum, 48 hours for P. vivax and P. ovale, and 72 hours for P. malariae.[9] The clinical manifestations of malaria, fever, and chills are associated with the synchronous rupture of the infected erythrocytes. The released merozoites go on to invade additional erythrocytes. Not all of the merozoites divide into schizonts; some differentiate into sexual forms, male and female gametocytes. These gametocytes are taken up by a female Anopheles mosquito during a blood meal. Within the mosquito midgut, the male gametocyte undergoes a rapid nuclear division, producing eight flagellated microgametes that fertilize the female macrogamete. The resulting ookinete traverses the mosquito gut wall and encysts on the exterior of the gut wall as an oocyst. Soon, the oocyst ruptures, releasing hundreds of sporozoites into the mosquito body cavity, where they eventually migrate to the mosquito salivary glands.


P. falciparum causes severe malaria via sequestration, a distinctive property not shared by any other human malaria. Within the 48-hour asexual blood stage cycle, the mature forms change the surface properties of infected red blood cells, causing them to stick to blood vessels (a process called cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, typically the brain in cerebral malaria.[10]

Microscopic appearance[edit]

Blood smear from a P. falciparum culture (K1 strain - asexual forms) - several red blood cells have ring stages inside them. Close to the center is a schizont and on the left a trophozoite.

Among medical professionals, the preferred method to diagnose malaria and determine which species of Plasmodium is causing the infection is by examination of a blood film under microscope in a laboratory. Each species has distinctive physical characteristics that are apparent under a microscope. In P. falciparum, only early (ring-form) trophozoites and gametocytes are seen in the peripheral blood. It is unusual to see mature trophozoites or schizonts in peripheral blood smears, as these are usually sequestered in the tissues. The parasitised erythrocytes are not enlarged, and it is common to see cells with more than one parasite within them (multiply parasitised erythrocytes). On occasion, faint, comma-shaped, red dots called "Maurer's dots" are seen on the red cell surface. The comma-shaped dots can also appear as pear-shaped blotches.

The P. falciparum genome[edit]

In 1995, a consortium, the Malaria Genome Project, was set up to sequence the genome of P. falciparum. The genome of its mitochondrion was reported in 1995, that of the nonphotosynthetic plastid known as the apicoplast in 1996,[11] and the sequence of the first nuclear chromosome (chromosome 2) in 1998. The sequence of chromosome 3 was reported in 1999, and the entire genome on 3 October 2002.[12] Annotated genome data can now be fully analyzed at several database resources including the UCSC Malaria Genome Browser, PlasmoDB and GeneDB. The roughly 24-megabase genome is extremely AT-rich (about 80%) and is organised into 14 chromosomes. Just over 5,300 genes were described.

Influence of P. falciparum on the human genome[edit]

The presence of the parasite in human populations caused selection in the human genome in a multitude of ways, as humans have been forced to develop resistance to the disease. Beet, a doctor working in Southern Rhodesia (now Zimbabwe) in 1948, first suggested that sickle-cell disease could offer some protection from malaria. This suggestion was reiterated by J. B. S. Haldane in 1949, who suggested that thalassaemia could provide similar protection. This hypothesis has since been confirmed and has been extended to hemoglobin C and hemoglobin E, abnormalities in ankyrin and spectrin (ovalocytosis, elliptocytosis), in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency, loss of the Gerbich antigen (glycophorin C) and the Duffy antigen on the erythrocytes, thalassemias and variations in the major histocompatibility complex classes 1 and 2 and CD32 and CD36.

P. falciparum and sickle-cell anemia[edit]

Further information: Genetic resistance to malaria

Individuals with sickle-cell anemia or sickle-cell trait do have reduced parasitemia when compared to wild-type individuals for the hemoglobin protein in red blood cells. These genetic deviations of hemoglobin from normal states provide protection against the deadly parasite that causes malaria.[13]

Of the six malarial parasites, P. falciparum causes the most fatal and medically severe form. Malaria is prevalent in tropical countries with an incidence of 300 million per year and a mortality of 1 to 2 million per year. Roughly 50% of all malarial infections are caused by P. falciparum.[14] Upon infection by a bite from an infected Anopheles mosquito, sporozoites devastate the human body by first infecting the liver. While in the liver, sporozoites undergo asexual development and merozoites are released into the bloodstream. The trophozoites further develop and reproduce by invading red blood cells. During the reproduction cycle, P. falciparum produces up to 40,000 merozoites in one day. Other blood sporozoans, such as P. vivax, P. ovale, and P. malariae, that infect humans and cause malaria do not have such a productive cycle for invasion. The process of bursting red blood cells does not have any symptoms, but destruction of the cells does cause anemia, since the bone marrow cannot compensate for the damage. When red blood cells rupture, hemozoin wastes cause cytokine release, chills, and then fever.[14]

P. falciparum trophozoites develop sticky knobs in red blood cells, which then adhere to endothelial cells in blood vessels, thus evading clearance in the spleen. The acquired adhesive nature of the red blood cells may cause cerebral malaria when sequestered cells prevent oxygenation of the brain. Symptoms of cerebral malaria include impaired consciousness, convulsions, neurological disorder, and coma. Additional complications from P. falciparum-induced malaria include advanced immunosuppression.[14]

Individuals with sickle-cell trait and sickle-cell anemia are privileged because they have altered sticky knobs. Parasitemia (the ability of a parasite to infect) occurs because merozoites of each parasite species that cause malaria invade the red blood cell in three stages: contact, attachment, and endocytosis.[15] Individuals suffering from sickle-cell anemia have deformed red blood cells that interfere with the attachment phase, and P. falciparum and the other forms of malaria have trouble with endocytosis.

These individuals have reduced attachment when compared to red blood cells with the normally functioning hemoglobin because of differing protein interactions. In normal circumstances, merozoites enter red blood cells through two PfEMP-1 protein-dependent interactions. These interactions promote the malaria inflammatory response associated with symptoms of chills and fever. When these proteins are impaired, as in sickle-cell cases, parasites cannot undergo cytoadherance interactions and cannot infect the cells; therefore, sickle-cell-anemic individuals and individuals carrying the sickle-cell trait have lower parasite loads and shorter time for symptoms than individuals expressing normal red blood cells.[16]

Individuals with sickle-cell anemia may also experience greatly reduced symptoms of malaria because P. falciparum trophozoites cannot bind to hemoglobin to form sticky knobs. Without knob-binding complexes, which is an exclusive feature of P. falciparum, red blood cells do not stick to endothelial walls of blood vessels, and infected individuals do not experience symptoms such as cerebral malaria.[15]

Many may wonder why natural selection has not phased out sickle-cell anemia. Individuals with sickle-cell trait are greatly desired in areas where malarial infections are endemic. Malaria kills between 1 and 2 million people per year. It is the leading cause of death among children in tropical regions. Individuals with sickle-cell deformities are able to fight Plasmodium parasite infections and do not become victims of malarial demise. Therefore, individuals expressing the genes and individuals carrying genes are selected to remain within the population.[17] It is no surprise that the incidence of sickle-cell anemia matches that of endemic regions for malarial infections.

Known vectors[edit]

Origins and evolution[edit]

The closest relative of P. falciparum is Plasmodium reichenowi, a parasite of chimpanzees. P. falciparum and P. reichenowi are not closely related to the other Plasmodium species that parasitize humans, or indeed mammals in general. These two species arguably originated from a parasite of birds.[19] More recent analyses do not support this, however, instead suggesting that the ability to parasitize mammals evolved only once within the genus Plasmodium.[20]

New evidence based on analysis of more than 1,100 mitochondrial, apicoplastic, and nuclear DNA sequences has suggested that P. falciparum may in fact have speciated from a lineage present in gorillas.[21][22][23]

According to this theory, P. falciparum and P. reichenowi may both represent host switches from an ancestral line that infected primarily gorillas; P. falciparum went on to infect primarily humans, while P. reichenowi specialized in chimpanzees. The ongoing debate over the evolutionary origin of P. falciparum will likely be the focus of continuing genetic study.[24]

A third species that appears to related to these two has been discovered: P. gaboni. This putative species is (as of 2009) known only from two DNA sequences and awaits a full species description before it can be regarded as valid.

Molecular clock analyses suggest P. falciparum is as old as the human line; the two species diverged at the same time as humans and chimpanzees.[25] However, low levels of polymorphism within the P. falciparum genome suggest a much more recent origin.[26] It may be that this discrepancy exists because P. falciparum is old, but its population recently underwent a great expansion.[27] Some evidence still indicates that P. reichenowi was the ancestor of P. falciparum.[28] The timing of this event is unclear at present, but it may have occurred about 10,000 years ago.

More recently, P. falciparum has evolved in response to human interventions. Most strains of malaria can be treated with chloroquine, but P. falciparum has developed resistance to this treatment. A combination of quinine and tetracycline has also been used, but some strains of P. falciparum have grown resistant to this treatment, as well. Different strains of P. falciparum have grown resistant to different treatments. Often, the resistance of the strain depends on where it was contracted. Many cases of malaria that come from parts of the Caribbean and west of the Panama Canal, as well as the Middle East and Egypt, can often be treated with chloroquine, since they have not yet developed resistance. Nearly all cases contracted in Africa, India, and Southeast Asia have grown resistant to this medication, and cases in Thailand and Cambodia have shown resistance to nearly all treatments. Often, the strain grows resistant to the treatment in areas where the use is not as tightly regulated.

Like most apicomplexans, malaria parasites harbor a plastid, an apicoplast, similar to plant chloroplasts, which they probably acquired by engulfing (or being invaded by) a eukaryotic alga, and retaining the algal plastid as a distinctive organelle encased within four membranes - (see endosymbiotic theory). The apicoplast is an essential organelle, thought to be involved in the synthesis of lipids and several other compounds, and it provides an attractive target for antimalarial drug development, in particular in light of the emergence of parasites resistant to chloroquine and other existing antimalarial agents.

During the erythrocyte stage, some P. falciparum merozoites develop into male and female gametocytes. Gametocyte production likely has an adaptive basis: it increases when conditions for asexual reproduction of the parasite worsen (e.g. upon exposure to immunological stress and/or antimalarial chemotherapy).[29] During the mosquito blood meal, male and female haploid gametocytes are ingested. These gametocytes quickly mature into gametes that fuse to form a diploid zygote (ookinete) that then encysts in the mosquito gut to form an oocyst where meiosis rapidly ensues.[30] Because fusion of gametes, zygote formation and meiosis must occur in the mosquito gut for the parasite to complete its life cycle, P. falciparum is an obligate sexual organism. While P. falciparum is a sexual organism, it is often self-fertilizing. Its population structure appears to predominantly reflect inbreeding.


Uncomplicated P. falciparum malaria[edit]

According to WHO guidelines 2010,[31] artemisinin-based combination therapies (ACTs) are the recommended first line antimalarial treatments for uncomplicated malaria caused by P. falciparum.[31] The following ACTs are recommended by the WHO:[31]

The choice of ACT in a country or region will be based on the level of resistance to the constituents in the combination.[31] Artemisinin and its derivatives should not be used as monotherapy in uncomplicated falciparum malaria.[31] As second-line antimalarial treatment, when initial treatment does not work or stops working, an alternative ACT known to be effective in the region is recommended, such as:

  • Artesunate plus tetracycline or doxycycline or clindamycin.[31]
  • Quinine plus tetracycline or doxycycline or clindamycin[31]

Any of these combinations are to be given for 7 days.[31]

In Africa, the overall treatment failure was less for dihydroartemisinin-piperaquine when compared to artemether-lumefantrine, and both drugs had PCR-adjusted failure rates of less than 5%. However, in Asian countries, dihydroartemisinin-piperaquine was found to be better tolerated, but as effective as artesunate plus mefloquine.[32]

For pregnant women, the recommended first-line treatment during the first trimester is quinine plus clindamycin for 7 days.[31] Artesunate plus clindamycin for 7 days is indicated if this treatment fails.[31] Still, an ACT is indicated only if this is the only treatment immediately available, or if treatment with 7-day quinine plus clindamycin fails or if there is uncertainty of compliance with a 7-day treatment.[31] In second and third trimesters, the recommended treatment is an ACT known to be effective in the country/region or artesunate plus clindamycin for 7 days, or quinine plus clindamycin for 7 days.[31] Lactating women should receive standard antimalarial treatment (including ACTs) except for dapsone, primaquine and tetracyclines.

In infants and young children, the recommended first-line treatment is ACTs, with attention to accurate dosing and ensuring the administered dose is retained.[31]

For travellers returning to nonendemic countries, any of the following is recommended:[31]

In severe falciparum malaria, rapid clinical assessment is recommended and confirmation of the diagnosis be made, followed by administration of full doses of parenteral antimalarial treatment without delay with whichever effective antimalarial is first available.[31]

For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended.[31] Quinine is an acceptable alternative if parenteral artesunate is not available.[31]

For children, especially in the malaria-endemic areas of Africa, any the following antimalarial medicines is recommended:[31]

  • artesunate IV or IM,
  • quinine (IV infusion or divided IM injection),
  • artemether IM - should be used only if none of the alternatives is available, as its absorption may be erratic.[31]

Parenteral antimalarials should be administered for a minimum of 24 hours in the treatment of severe malaria, irrespective of the patient's ability to tolerate oral medication earlier.[31] Thereafter, complete treatment is recommended by giving a complete course of any of the following:[31]

  • an ACT
  • artesunate plus clindamycin or doxycycline
  • quinine plus clindamycin or doxycycline

If complete treatment of severe malaria is not possible, patients should be given prereferral treatment and referred immediately to an appropriate facility for further treatment. The following are options for prereferral treatment:[31]

  • rectal artesunate
  • quinine IM
  • artesunate IM
  • artemether IM

History of falciparum malaria treatment[edit]

Attempts to make synthetic antimalarials began in 1891. Atabrine, developed in 1933, was used widely throughout the Pacific in World War II, but was deeply unpopular because of the yellowing of the skin it caused. In the late 1930s, the Germans developed chloroquine, which went into use in the North African campaigns. Mao Zedong encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. Artemisinin was discovered in the 1970s based on a medicine described in China in the year 340. This new drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment. In 1976, P. falciparum was successfully cultured in vitro for the first time, which facilitated the development of new drugs substantially.[33] A 2008 study highlighted the emergence of artemisinin-resistant strains of P.falciparum in Cambodia.[34]


Although an antimalarial vaccine is urgently needed, infected individuals never develop a sterilizing (complete) immunity, making the prospects for such a vaccine dim. The parasites live inside cells, where they are largely hidden from the immune response. Infection has a profound effect on the immune system including immune suppression. Dendritic cells suffer a maturation defect following interaction with infected erythrocytes and become unable to induce protective liver-stage immunity. Infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The var gene products, a group of highly expressed surface antigens, bind the Fab and Fc fragments of human immunoglobulins in a fashion similar to protein A to Staphylococcus aureus, which may offer some protection to the parasite from the human immune system. Despite the poor prospects for a fully protective vaccine, it may be possible to develop a vaccine that would reduce the severity of malaria for children living in endemic areas.

See also[edit]


  1. ^ Coatney GR, Collins WE, Warren M, Contacos PG (1971). "22 Plasmodium falciparum (Welch, 1897)". The primate malarias. Division of Parasitic Disease, CDC. p. 263. 
  2. ^ Rich, S. M.; Leendertz, F. H.; Xu, G.; Lebreton, M.; Djoko, C. F.; Aminake, M. N.; Takang, E. E.; Diffo, J. L. D.; Pike, B. L.; Rosenthal, B. M.; Formenty, P.; Boesch, C.; Ayala, F. J.; Wolfe, N. D. (2009). "The origin of malignant malaria". Proceedings of the National Academy of Sciences 106 (35): 14902–14907. doi:10.1073/pnas.0907740106. PMC 2720412. PMID 19666593.  edit
  3. ^ Perkins, D. J.; Were, T.; Davenport, G. C.; Kempaiah, P.; Hittner, J. B.; Ong'Echa, J. M. (2011). "Severe malarial anemia: Innate immunity and pathogenesis". International journal of biological sciences 7 (9): 1427–1442. doi:10.7150/ijbs.7.1427. PMC 3221949. PMID 22110393.  edit
  4. ^ Perlmann, P; Troye-Blomberg, M (2000). "Malaria blood-stage infection and its control by the immune system". Folia biologica 46 (6): 210–8. PMID 11140853. 
  5. ^ "Factsheet on the World Malaria Report 2014". World Health Orgnization. 2014. Retrieved 2 February 2015. 
  6. ^ WHO (2014). World Malaria Report 2014. Geneva, Switzerland: World Health Organization. pp. 32–42. ISBN 978-92-4156483-0. 
  7. ^ "World Malaria Report 2008". World Health Organisation. 2008. p. 10. Retrieved 2009-08-17. 
  8. ^ http://www.ijern.com/images/February-2013/13.pdf
  9. ^ Biodiversity of the Malaria in the World, Sylvie Manguin et al. Editorial John Libbey, 2008. p. 23
  10. ^ Dondorp AM, Pongponratn E, White NJ (February 2004). "Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology". Acta Trop. 89 (3): 309–17. doi:10.1016/j.actatropica.2003.10.004. PMID 14744557. 
  11. ^ Wilson RJ; Denny PW; Preiser PR et al. (August 1996). "Complete gene map of the plastid-like DNA of the malaria parasite Plasmodium falciparum". Journal of Molecular Biology 261 (2): 155–72. doi:10.1006/jmbi.1996.0449. PMID 8757284. 
  12. ^ Gardner MJ; Hall N; Fung E; and others; Berriman, Matthew; Hyman, Richard W.; Carlton, Jane M.; Pain, Arnab; Nelson, Karen E.; Bowman, Sharen; Paulsen, Ian T.; James, Keith; Eisen, Jonathan A.; Rutherford, Kim; Salzberg, Steven L.; Craig, Alister; Kyes, Sue; Chan, Man-Suen; Nene, Vishvanath; Shallom, Shamira J.; Suh, Bernard; Peterson, Jeremy; Angiuoli, Sam; Pertea, Mihaela; Allen, Jonathan; Selengut, Jeremy; Haft, Daniel; Mather, Michael W.; Vaidya, Akhil B. et al. (October 2002). "Genome sequence of the human malaria parasite Plasmodium falciparum". Nature 419 (6906): 498–511. Bibcode:2002Natur.419..498G. doi:10.1038/nature01097. PMID 12368864. 
  13. ^ (Allison, 1954).
  14. ^ a b c Roberts and Janovy Jr., 2005
  15. ^ a b Cholera, R., Brittain, N., Gillrie, M. et al. (2007)
  16. ^ Mockenhaupt, 2004
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Sources and further reading[edit]


Spatial distribution[edit]

Blood slides[edit]

Case histories[edit]

Pathology due to Plasmodium falciparum[edit]


Plasmodium falciparum genome data[edit]


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Plasmodium falciparum biology

Plasmodium falciparum has been the focus of much research due to it being the causative agent of malaria. This article describes some of the recent findings surrounding the unique biology of this organism.

Life Cycle[edit]

Plasmodium falciparum has a complicated life-cycle, requiring both a human and a mosquito host, and differentiating multiple times during its transmission/infection process.[1]

Plasmodium life cycle[2]

Human infection[edit]

P. falciparum is transmitted to humans by the females of the Anopheles species of mosquito. There are about 460 species of Anopheles mosquito, but only 68 transmit malaria. Anopheles gambiae is one of the best malaria vectors since it is long-lived, prefers feeding on humans, and lives in areas near human habitation. A. gambiae is found in Africa.[3]

Prior to transmission, Plasmodium falciparum resides within the salivary gland of the mosquito. The parasite is in its sporozoite stage at this point. As the mosquito takes its blood meal, it injects a small amount of saliva into the skin wound. The saliva contains antihemostatic and anti-inflammatory enzymes that disrupt the clotting process and inhibit the pain reaction.[4] Typically, each infected bite contains 5-200 sporozoites which proceed to infect the human.[3] Once in the human bloodstream, the sporozoites only circulate for a matter of minutes before infecting liver cells.

Liver stage[edit]

After circulating in the bloodstream, the P. falciparum sporozoites enter hepatocytes. At this point, the parasite loses its apical complex and surface coat, and transforms into a trophozoite. Within the parasitophorous vacuole of the hepatocyte, P. falciparum undergoes schizogonic development. In this stage, nucleus divides multiple times with a concomitant increase in cell size, but without cell segmentation. This exoerythrocytic schizogony stage of P. falciparum has a minimum duration of roughly 5.5 days. After segmentation, the parasite cells are differentiated into merozoites.[5]

After maturation, the merozoites are released from the hepatocytes and enter the erythrocytic portion of their life-cycle. Note that these cells do not reinfect hepatocytes.

Erythrocytic stage[edit]


After release from the hepatocytes, the merozoites enter the bloodstream prior to infecting red blood cells. At this point, the merozoites are roughly 1.5 μm in length and 1 μm in diameter, and use the apicomplexan invasion organelles (apical complex, pellicle and surface coat) to recognize and enter the host erythrocyte.

The parasite first binds to the erythrocyte in a random orientation. It then reorients such that the apical complex is in proximity to the erythrocyte membrane. A tight junction is formed between the parasite and erythrocyte. As it enters the red blood cell, the parasite forms a parasitophorous vesicle, to allow for its development inside the erythrocyte.[6]


After invading the erythrocyte, the parasite loses its specific invasion organelles (apical complex and surface coat) and de-differentiates into a round trophozoite located within a parasitophorous vacuole in the red blood cell cytoplasm. The young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing schizogonic division.[7]


At the schizont stage, the parasite replicates its DNA multiple times without cellular segmentation. These schizonts then undergo cellular segmentation and differentiation to form roughly 16-18 merozoite cells in the erythrocyte.[7] The merozoites burst from the red blood cell, and proceed to infect other erythrocytes. The parasite is in the bloodstream for roughly 60 seconds before it has entered another erythrocyte.[6]

This infection cycle occurs in a highly synchronous fashion, with roughly all of the parasites throughout the blood in the same stage of development. This precise clocking mechanism has been shown to be dependent on the human host's own circadian rhythm.[8] Specifically, human body temperature changes, as a result of the circadian rhythm, seem to play a role in the development of P. falciparum within the erythrocytic stage.

Within the red blood cell, the parasite metabolism depends greatly on the digestion of hemoglobin.

Infected erythrocytes are often sequestered in various human tissues or organs, such as the heart, liver and brain. This is caused by parasite-derived cell surface proteins being present on the red blood cell membrane, and it is these proteins that bind to receptors on human cells. Sequestration in the brain causes cerebral malaria, a very severe form of the disease, which increases the victim's likelihood of death.

The parasite can also alter the morphology of the red blood cell, causing knobs on the erythrocyte membrane.

Gametocyte differentiation[edit]

During the erythrocytic stage, some merozoites develop into male and female gametocytes. This process is called gametocytogenesis.[9] The specific factors and causes underlying this sexual differentiation are largely unknown. These gametocytes take roughly 8–10 days to reach full maturity. Note that the gametocytes remain within the erythrocytes until taken up by the mosquito host.

Mosquito stage[edit]

P. falciparum is taken up by the female Anopheles mosquito as it takes its bloodmeal from an infected human.


Upon being taken up by the mosquito, the gametocytes leave the erythrocyte shell and differentiate into gametes. The female gamete maturation process entails slight morphological changes, as it becomes enlarged and spherical. On the other hand, the male gamete maturation involves significant morphological development. The male gamete's DNA divides three times to form eight nuclei. Concurrently, eight flagella are formed. Each flagella pairs with a nucleus to form a microgamete, which separates from the parasite cell. This process is referred to as exflagellation.

Gametogenesis has been shown to be caused by: 1) a sudden drop in temperature upon leaving the human host, 2) a rise in pH within the mosquito, and 3) xanthurenic acid within the mosquito.[10] Gametocyte production has been proposed to have an adaptive basis since it increases when conditions for asexual reproduction of the parasite worsen (e.g. upon exposure to immunological stress and/or antimalarial chemotherapy).[11]


During the mosquito blood meal, male and female haploid gametocytes are ingested. Fertilization of the female gamete by the male gamete occurs rapidly after gametogenesis. The fertilization event produces a zygote. The zygote then develops into an ookinete. The zygote and ookinete are the only diploid stages of P. falciparum.


The diploid ookinete is an invasive form of P. falciparum within the mosquito. It traverses the peritrophic membrane of the mosquito midgut and cross the midgut epithelium. Once through the epithelium, the ookinete enters the basil lamina, and forms an oocyst where meiosis takes place.

During the ookinete stage, genetic recombination can occur. This takes place if the ookinete was formed from male and female gametes derived from different populations. This can occur if the human host contained multiple populations of the parasite, or if the mosquito fed from multiple infected individuals within a short time-frame. Because fusion of gametes, zygote formation and meiosis must occur in the mosquito gut for the parasite to complete its life cycle, P.falciparum is an obligate sexual organism.


Over the period of a 1–3 weeks, the oocyst grows to a size of tens to hundreds of micrometres. During this time, multiple nuclear divisions occur. After oocyst maturation is complete, the oocyst divides to form multiple haploid sporozoites. Immature sporozoites break through the oocyst wall into the haemolymph. The sporozoites then migrate to the salivary glands and complete their differentiation. Once mature, the sporozoites can proceed to infect a human host during a subsequent mosquito bite.

Population genetic structure[edit]

By studying genetic polymorphisms in the oocysts of mosquitoes in high-infection regions, the population genetic structure of P. falciparum can be determined.[12][13] Razakandrainibe et al.[12] (2007) examined oocysts from Anopheles gambiae mosquito populations in Kenya where malarial transmission is perennial and intense. The oocyts are the only stage of the parasite’s life cycle where diploidy and the immediate products of meiosis can be observed. They found a strong deviation from panmixia (random mating) consistent with a high level of inbreeding of P. falciparum. A contributing factor to this inbreeding was the observed high rate of self-fertilization, about 25% of matings. These findings were confirmed and extended by Annan et al.[13] (2007) who compared two mosquito vectors, Anopheles gambiae and Anopheles funestus, from three widely separated African sites. Thus, despite being an obligate sexual organism, the population structure of P. falciparum appears to predominantly reflect inbreeding.

Cell Biology[edit]

Cell Division[edit]

Cell division occurs through a process known as schizogony. This is a type of mitotic division in which multiple rounds of nuclear divisions occur before the cytoplasm segments.

Apical complex[edit]



Parasitophorous Vacuole[edit]

Within a red blood cell, P. falciparum resides inside the parasitophorous vacuole. This is formed during erythrocyte invasion.

The proteins originating in the parasite pass through the membrane of the parasitophorous vacuole, and are transported to the cytoplasm or membrane of the erythrocyte.[14] This transport mechanism is largely unknown.


Plasmodium falciparum, and other members of the apicomplexa phylum, contain an organelle called the apicoplast.[14] The apicoplast is an essential plastid, homologous to a chloroplast, although the apicoplast is not photosynthetic. Evolutionarily, it is thought to have derived through secondary endosymbiosis.

The function of the apicoplast remains to be fully determined, but it appears to be involved in the metabolism of fatty acids, isoprenoids, and heme.[14]

The apicoplast contains a 35-kb genome, which encodes for 30 proteins. Other, nuclear-encoded, proteins are transported into the apicoplast using a specific signal peptide. It is estimated that 551, or roughly 10%, of the predicted nuclear-encoded proteins are targeted to the apicoplast.[14]

As humans do not harbor apicoplasts, this organelle and its constituents are seen as a possible target for antimalarial drugs.


The genome of Plasmodium falciparum (clone 3D7) was fully sequenced in 2002.[14] The parasite has a 23 megabase genome, divided into 14 chromosomes.[14] The genome codes for approximately 5,300 genes. About 60% of the putative proteins have little or no similarity to proteins in other organisms, and thus currently have no functional assignment.[14] It is estimated 52.6% of the genome is a coding region, with 53.9% of the putative genes containing at least one intron.[14]


It is haploid during nearly all stages of its life-cycle, except for a brief period after fertilization when it is diploid from the ookinete to sporogenic stages within the mosquito gut.

AT Richness[edit]

The P. falciparum genome has an AT content of roughly 80.6%.[14] Within the intron and intergenic regions, this AT composition rises to roughly 90%. The putative exons contain an AT content of 76.3%. The parasite's AT content is very high in comparison to other organisms. For example, the entire genomes of Saccharomyces cerevisiae and Arabidopsis thaliana have AT contents of 62% and 65%, respectively.[14]


Subtelomeric regions[edit]

The subtelomeric regions of P. falciparum chromosomes show a high degree of conservation within the genome, and contain significant amounts of repeated structure.[14] These conserved regions can be divided into five subtelomeric blocks. The blocks contain tandem repeats in addition to non-repetitive regions.

Many genes involved in antigenic variation are located in the subtelomeric regions of the chromosomes. These are divided into the var, rif, and stevor families. Within the genome, there exist 59 var, 149 rif, and 28 stevor genes, along with multiple pseudogenes and truncations.[14]


Phaseogram of Plasmodium falciparum intraerythrocytic development cycle transcriptome[15]

A transcriptome analysis has been conducted on the intraerythrocytic development cycle of P. falciparum.[15] Roughly 60% of the genome is transcriptionally active during this portion of the parasite's life cycle. Whereas many genes appear to have stable mRNA levels throughout the cycle, many of the genes are transcriptionally regulated in a continuous cascade.

The transition from early trophozoite to trophozoite to schizont correlates with the ordered induction of genes related to transcription/translation machinery, metabolic synthesis, energy metabolism, DNA replication, protein degradation, plastid functions, merozoite invasion, and motility.

Closely adjacent genes along the chromosome do not exhibit common transcription characteristics. Thus, genes are likely individually regulated along the parasite chromosome.

Conversely, the apicoplast genome is polycistronic and most of its genes are coexpressed during the intraerythrocytic development cycle.[15]


There are 5,268 predicted proteins in Plasmodium falciparum, and roughly 60% share little or no similarity to proteins in other organisms and thus are without functional assignment.[14] Of the predicted proteins, 31% contain at least one transmembrane domain, and 17.3% have a signal peptide or signal anchor.[14]

It is estimated that 10.4% of the proteome is targeted to the apicoplast.[14]

It is estimated that 4.7% of the proteome is targeted to the mitochondria.[14]

The parasite has different subsets of its proteome expressed during various stages of its developmental cycle.[16] In one study, of the 2,415 proteins were identified in four stages(sporozoite, merozoite, trophozoite, gametocyte), representing 46% of the theoretical number of proteins.[16] Only 6% of the proteins were found in all of the four stages. Of the proteins found, 51% were annotated as hypothetical proteins.

Merozoites contained high levels of cell recognition and invasion proteins. Trophozoites contained proteins implicated in erythrocyte remodeling and hemoglobin digestion. Gametocytes contained high amounts of gametocyte-specific transcription factors and cell cycle/DNA processing proteins. The gametocytes had low levels of polymorphic surface antigens. Sporozoites contained large amounts of proteins related to invasion, as well as members of the var and rif families.[16]


While all of the metabolic pathways of Plasmodium falciparum have yet to be fully elucidated, the presence and components of many can be predicted through genomic analysis.[14]

Hemoglobin metabolism[edit]

During the erythrocytic stage of the parasite's life cycle, it uses intracellular hemoglobin as a food source. The protein is broken down into peptides, and the heme group is released and detoxified by biocrystallization in the form of hemozoin.

Heme biosynthesis by the parasite has been reported.[17]

Carbohydrate metabolism[edit]

During erythrocytic stages, the parasite produces its energy mainly through anaerobic glycolysis, with pyruvate being converted into lactate.[14]

Genes encoding for the TCA cycle enzymes are present in the genome, but it is unclear whether the TCA cycle is used for oxidation of glycolytic products to be used for energy production, or for metabolite intermediate biosynthesis.[14] It has been hypothesized that the main function of the TCA cycle in P. falciparum is for production of succinyl-CoA, to be used in heme biosynthesis.[14]

Genes for nearly all of the pentose phosphate pathway enzymes have been identified from the genome sequence.

Protein metabolism[edit]

It has been hypothesized that the parasite obtains all, or nearly all, of its amino acids by salvaging from the host or through the degradation of hemoglobin. This is supported by the fact that genomic analysis has found no enzymes necessary for amino acid biosynthesis, except for glycine-serine, cysteine-alanine, aspartate-asparagine, proline-ornithine, and glutamine-glutamate interconversions.[14]

Lipid metabolism[edit]

Nucleotide metabolism[edit]

P. falciparum is unable to biosynthesize purines.[14] Instead, the parasite is able to transport and interconvert host purines.

Conversely, the parasite can produce pyrimidines de novo using glutamine, bicarbonate, and aspartate.[14]

Human immune system evasion[edit]

var family[edit]

The var genes encode for the P. falciparum erythrocyte membrane protein 1 (PfEMP1) proteins. The genes are found in the subtelomeric regions of the chromosomes. There exist an estimated 59 var genes within the genome.[14]

The proteins encoded by the var genes are ultimately transported to the erythrocyte membrane and cause the infected erythrocytes to adhere to host endothelial receptors. Due to transcriptional switching between var genes, antigenic variation occurs which enables immune evasion by the parasite.

rif family[edit]

The rif genes encode for repetitive interspersed family (rifin) proteins. The genes are found in the subtelomeric regions of the chromosomes. There exist an estimated 149 rif genes within the genome.[14]

Rifin protein are ultimately transported to the erythrocyte membrane. The function of these proteins is currently unknown.

stevor family[edit]

The stevor genes encode for the sub-telomeric variable open reading frame (stevor) proteins. The genes are found in the subtelomeric regions of the chromosomes. There exist an estimated 28 stevor genes within the genome.[14]

The function of the stevor proteins is currently unknown.



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