Plasmodium falciparum is a
protozoanProtozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
parasite, one of the species of
PlasmodiumPlasmodium is a genus of parasitic protists. 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.Of the over 200 known...
that cause
malariaMalaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
in humans. It is transmitted by the female
AnophelesAnopheles is a genus of mosquito. There are approximately 460 recognized species: while over 100 can transmit human malaria, only 30–40 commonly transmit parasites of the genus Plasmodium, which cause malaria in humans in endemic areas...
mosquitoMosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...
. Malaria caused by this species (also called malignant or falciparum malaria) is the most dangerous form of malaria, with the highest rates of complications and mortality. As of 2006 there were an estimated 247 million human malarial infections (98% in Africa, 85% being 5 years or younger). It is more prevalent in sub-Saharan Africa than in other regions of the world; in most African countries, more than 75% of cases were due to
P. falciparum, whereas in most other countries with malaria transmission, other less virulent Plasmodial species predominate. Almost all global malarial deaths are caused by
P. falciparum.
Background
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 LancisiGiovanni Maria Lancisi was an Italian physician, epidemiologist and anatomist who made a correlation between the presence of mosquitoes and the prevalence of malaria...
(1717) of
malariaMalaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
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
LaveranCharles Louis Alphonse Laveran was a French physician.In 1880, while working in the military hospital in Constantine, Algeria, he discovered that the cause of malaria is a protozoan, after observing the parasites in a blood smear taken from a patient who had just died of malaria.He also helped...
on November 6, 1880 at a military hospital in
Constantine, AlgeriaConstantine is the capital of Constantine Province in north-eastern Algeria. It was the capital of the same-named French département until 1962. Slightly inland, it is about 80 kilometres from the Mediterranean coast, on the banks of Rhumel river...
, when he discovered a microgametocyte exflagellating.
Patrick MansonSir Patrick Manson was a Scottish physician who made important discoveries in parasitology and was the founder of the tropical medicine field....
(1894) hypothesised that mosquitoes could transmit malaria. This hypothesis was experimentally confirmed independently by
Giovanni Battista GrassiGiovanni Battista Grassi was an Italian zoologist, known for work demonstrating that mosquitos carry the malaria parasite Plasmodium in their digestive tract, on the embryological development of honey bees, on parasites, particularly the vine parasite phylloxera, migrations and metamorphosis in...
and
Ronald RossSir Ronald Ross KCB FRS was a British doctor who received the Nobel Prize for Physiology or Medicine in 1902 for his work on malaria. He was the first Indian-born person to win a Nobel Prize...
in 1898. Grassi (1900) proposed an exerythrocytic stage in the life cycle, later confirmed by Short, Garnham, Covell and Shute (1948), who found
Plasmodium vivaxPlasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
in the human liver.
Around the world, malaria is the most significant
parasitic diseaseA parasitic disease is an infectious disease caused or transmitted by a parasite. Many parasites do not cause diseases. Parasitic diseases can affect practically all living organisms, including plants and mammals...
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 of 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.
While there are no effective vaccines 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
cinchonaCinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...
bark for treating malaria: The native Indians of
PeruPeru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....
and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "Jesuits' bark" to
EnglandEngland is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
: Its first recorded use there was by Dr John Metford of
NorthamptonNorthampton is a large market town and local government district in the East Midlands region of England. Situated about north-west of London and around south-east of Birmingham, Northampton lies on the River Nene and is the county town of Northamptonshire. The demonym of Northampton is...
in 1656.
MortonRichard Morton was an English physician who was the first to state that tubercles were always present in the tuberculosis disease of the lungs. In Morton's time, this wasting disease was termed consumption, or by its Greek name of phthisis...
(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
quinineQuinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
from the
cinchonaCinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...
bark and
PelletierPierre-Joseph Pelletier was a French chemist who did notable research on vegetable alkaloids, and was the co-discoverer of quinine and strychnine.- Further reading :...
and
CaventouJoseph Bienaimé Caventou was a French chemist.He was a professor at the École de Pharmacie in Paris. He collaborated with Pierre-Joseph Pelletier in a Parisian laboratory located behind an apothecary. He was a pioneer in the use of mild solvents to isolate a number of active ingredients from...
(1820) in
FranceThe French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
extracted pure
quinineQuinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
alkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s, which they named quinine and
cinchonineCinchonine is an alkaloid with molecular formula C19H22N2O used in asymmetric synthesis in organic chemistry. It is a stereoisomer and pseudo-enantiomer of cinchonidine....
.
Plasmodium life cycle
The life cycle of all Plasmodium species is complex. Infection in humans begins with the bite of an infected female Anopheline 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 which 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 life cycle depends on the parasite species: irregular cycle for
P. vivax, and
P. ovale, 48 hours for
P. falciparum and 72 hours for
P. malariae. The clinical manifestations of malaria, fever and chills, are associated with the synchronous rupture of the infected erythrocyte. 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 anophylean mosquito during a blood meal. Within the mosquito midgut, the male gametocyte undergoes a rapid nuclear division, producing 8 flagellated microgametes which fertilize the female macrogamete. The resulting ookinete traverses the mosquito gut wall and encysts on the exterior of the gut wall as a oocyst. Soon the oocyst ruptures, releasing hundreds of sporozoites into the mosquito body cavity where they eventually migrate to the mosquito salivary gland.
Pathogenesis
Plasmodium falciparum causes severe malaria via a distinctive property not shared by any other human malaria, that of sequestration. 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.
Microscopic appearance
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 filmA blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
under microscope in a laboratory. Each species has distinctive physical characteristics that are apparent under a
microscopeA microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...
. In
P. falciparum, only early (ring-form) trophozoites and
gametocyteA gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called spermatocytes, and female gametocytes are called oocytes....
s 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 Plasmodium falciparum genome
In 1995, a consortium, the malaria
genomeIn modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
project (MGP), was set up to sequence the genome of
P. falciparum. The genome of the parasite
mitochondrionIn cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
was reported in 1995, that of the non-photosynthetic
plastidPlastids are major organelles found in the cells of plants and algae. Plastids are the site of manufacture and storage of important chemical compounds used by the cell...
known as the
apicoplastAn apicoplast is a derived non-photosynthetic plastid found in most Apicomplexa, including malaria parasites such as Plasmodium falciparum, but not in others such as Cryptosporidium. It originated from an algae through secondary endosymbiosis...
in 1996, and the sequence of the first nuclear
chromosomeA chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(Chromosome 2) in 1998. The sequence of chromosome 3 was reported in 1999 and the entire genome on 3 October 2002. Annotated genome data can now be fully analyzed at several database resources including the
http://areslab.ucsc.edu/UCSC Malaria Genome BrowserUCSC Malaria Genome Browser is a bioinformatic research tool to study the malaria genome, developed by Hughes Undergraduate Research Laboratory together with the laboratory of Prof. Manuel Ares Jr. at the University of California, Santa Cruz....
],
PlasmoDB and
GeneDB. The ~24 megabase genome is extremely AT rich (~80%) and is organised into 14 chromosomes: just over 5,300 genes were described.
Influence of Plasmodium falciparum on the human genome
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 RhodesiaSouthern Rhodesia was the name of the British colony situated north of the Limpopo River and the Union of South Africa. From its independence in 1965 until its extinction in 1980, it was known as Rhodesia...
(now
ZimbabweZimbabwe is a landlocked country located in the southern part of the African continent, between the Zambezi and Limpopo rivers. It is bordered by South Africa to the south, Botswana to the southwest, Zambia and a tip of Namibia to the northwest and Mozambique to the east. Zimbabwe has three...
) in 1948, first suggested that
sickle-cell diseaseSickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
could offer some protection to malaria. This suggestion was reiterated by
J. B. S. HaldaneJohn Burdon Sanderson Haldane FRS , known as Jack , was a British-born geneticist and evolutionary biologist. A staunch Marxist, he was critical of Britain's role in the Suez Crisis, and chose to leave Oxford and moved to India and became an Indian citizen...
in 1949 who suggested that thalassaemia could provide similar protection. This hypothesis has since been confirmed and has been extended to
hemoglobin CHemoglobin C is an abnormal hemoglobin with substitution of a lysine residue for a glutamic acid residue at the 6th position of the β-globin chain.-Clinical significance:...
and hemoglobin E, abnormalities in
ankyrinAnkyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
and
spectrinSpectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure...
(
ovalocytosisSoutheast Asian ovalocytosis is a form of hereditary elliptocytosis common in some communities in Malaysia and Papua New Guinea, as it confers some resistance to cerebral Falciparum Malaria.-Southeast Asian ovalocytosis:...
, elliptocytosis), in
glucose-6-phosphate dehydrogenase deficiencyGlucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...
and
pyruvate kinase deficiencyPyruvate kinase deficiency, also called erythrocyte pyruvate kinase deficiency, is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells and causes them to deform into echinocytes on peripheral blood smears.Both autosomal dominant and recessive...
, loss of the Gerbich antigen (
glycophorin CGlycophorin C plays a functionally important role in maintaining erythrocyte shape and regulating membrane material properties, possibly through its interaction with protein 4.1. Moreover, it has previously been shown that membranes deficient in protein 4.1 exhibit decreased content of glycophorin C...
) and the
Duffy antigenDuffy antigen/chemokine receptor also known as Fy glycoprotein or CD234 is a protein that in humans is encoded by the DARC gene....
on the erythrocytes,
thalassemiaThalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin...
s and variations in the
major histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
classes 1 and 2 and
CD32CD32 is a surface receptor protein and part of a large population of B cell co-receptors, which act to modulate signaling.It has a low-affinity for IgG antibodies and down-regulates antibody production in the presence of IgG...
and
CD36CD36 is an integral membrane protein found on the surface of many cell types in vertebrate animals and is also known as FAT, SCARB3, GP88, glycoprotein IV and glycoprotein IIIb . CD36 is a member of the class B scavenger receptor family of cell surface proteins...
.
Plasmodium falciparum and sickle cell anemia
Individuals with sickle cell anemia and individuals with sickle cell trait do have reduced parasitemia when compared to wild-typed individuals for the hemoglobin protein in red blood cells. Studies have shown these genetic deviations of hemoglobin from normal states provide protection against the deadly parasite that causes malaria (Allison, 1954).
Of the four malarial parasites,
Plasmodium 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 rate of 1 to 2 million per year. Roughly 50% of all malarial infections are caused by
Plasmodium falciparum (Roberts and Janovy Jr., 2005). Upon infection via 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 blood stream. The trophozoites further develop and reproduce by invading red blood cells. During the reproduction cycle,
Plasmodium falciparum produces up to 40,000 merozoites in one day. Other blood sporozoans, such as
Plasmodium vivax,
Plasmodium ovale, and
Plasmodium 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, however 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 (Roberts and Janovy Jr., 2005).
Plasmodium 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 (Brown University). Additional complications from
Plasmodium falciparum induced malaria include advanced immunosuppression (Roberts and Janovy Jr., 2005).
Individuals with sickle cell trait and sickle cell anemia are privileged because they have altered sticky knobs. Research by Cholera, R., Brittain, N., Gillrie, M. et al. (2007) has shown that parasitemia (the ability of a parasite to infect) because merozoites of each parasite species that cause malaria invade the red blood cell in three stages: contact, attachment, and endocytosis. Individuals suffering from sickle cell anemia have deformed red blood cells that interfere with the attachment phase and
Plasmodium 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 (Mockenhaupt, 2004).
Individuals with sickle cell anemia may also experience greatly reduced symptoms of malaria because
Plasmodium falciparum trophozoites cannot bind to hemoglobin in order to form sticky knobs. Without knob binding complexes, which is an exclusive feature of
Plasmodium falciparum, red blood cells do not stick to endothelial walls of blood vessels, and infected individuals do not experience symptoms such as cerebral malaria (Cholera, R., Brittain, N., Gillrie, M. et al. 2007).
Many may wonder why natural selection has not phased out sickle cell anemia. The answer lies within answers generated by Cholera, R., Brittain, N., Gillrie, M. et al. (2007). 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 (Allison 1964). It is no surprise that the incidence of sickle cell anemia matches endemic regions for malarial infections.
Known vectors
Anopheles gambiaeAnopheles gambiae is a complex of at least seven morphologically distinguishable species of mosquitoes in the genus Anopheles. This complex was recognised in the 1960s and includes the most important vectors of malaria in sub-Saharan Africa and the most efficient malaria vectors known.This species...
(Principal vector)
Anopheles albimanusAnopheles albimanus is a species of mosquito.-Habitat:Larvae of this species live in a wide range of permanent freshwater habitats. They are, however, salt tolerant. They live in sites that contain abundant amounts of floating, emergent vegetation. The larvae can also live in floating algae and scum...
Anopheles freeborni
Anopheles maculatus
Anopheles stephensiAnopheles albimanus is a species of mosquito....
Origins and evolution
The closest relative of
Plasmodium falciparum is
Plasmodium reichenowi, a parasite of
chimpanzeeChimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s.
P. falciparum and
P. reichenowi are not closely related to the other
Plasmodium species that parasitize humans, or indeed mammals generally. It has been argued that these two species originated from a parasite of birds. More recent analyses do not support this, however, instead suggesting that the ability to parasitize mammals evolved only once within the genus
Plasmodium.
New evidence based on analysis of more than 1,100
mitochondrialMitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
,
apicoplastAn apicoplast is a derived non-photosynthetic plastid found in most Apicomplexa, including malaria parasites such as Plasmodium falciparum, but not in others such as Cryptosporidium. It originated from an algae through secondary endosymbiosis...
ic, and
nuclearNuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
DNA sequences has suggested that
Plasmodium falciparum may in fact have speciated from a lineage present in gorillas.
According to this theory,
P. falciparum and
P. reichenowi may both represent host switches from an ancestral line that primarily infected gorillas;
P. falciparum went on to primarily infect humans while
P. reichenowi specialized in chimpanzees. The ongoing debate over the evolutionary origin of
Plasmodium falciparum will likely be the focus of continuing genetic study.
A third species has been discovered that appears to related to these two:
Plasmodium gaboni. This putative species is currently (2009) known only from two DNA sequences and awaits a full species description before it can be regarded as valid.
Molecular clockThe molecular clock is a technique in molecular evolution that uses fossil constraints and rates of molecular change to deduce the time in geologic history when two species or other taxa diverged. It is used to estimate the time of occurrence of events called speciation or radiation...
analyses suggest that
P. falciparum is as old as the human line; the two species diverged at the same time as humans and chimpanzees. However, low levels of polymorphism within the
P. falciparum genome suggest a much more recent origin. It may be that this discrepancy exists because
P. falciparum is old, but its population recently underwent a great expansion.
Some evidence still indicates that
P. reichenowi was the ancestor of
P. falciparum. The timing of this event is unclear at present but it has been proposed that 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 there are strains of
P. falciparum that 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 there have been cases in Thailand and Cambodia in which the strain has been resistant to nearly all treatments. Often the strain grows resistant to the treatment in areas where the use is not as tightly regulated.
Like most
ApicomplexaThe Apicomplexa are a large group of protists, most of which possess a unique organelle called apicoplast and an apical complex structure involved in penetrating a host's cell. They are unicellular, spore-forming, and exclusively parasites of animals. Motile structures such as flagella or...
, malaria parasites harbor a plastid similar to plant
chloroplastChloroplasts are organelles found in plant cells and other eukaryotic organisms that conduct photosynthesis. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis.Chloroplasts are green...
s, which they probably acquired by engulfing (or being invaded by) a eukaryotic alga, and retaining the algal plastid as a distinctive
organelleIn cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
encased within four membranes (see
endosymbiotic theoryThe endosymbiotic theory concerns the mitochondria, plastids , and possibly other organelles of eukaryotic cells. According to this theory, certain organelles originated as free-living bacteria that were taken inside another cell as endosymbionts...
). The
apicomplexaThe Apicomplexa are a large group of protists, most of which possess a unique organelle called apicoplast and an apical complex structure involved in penetrating a host's cell. They are unicellular, spore-forming, and exclusively parasites of animals. Motile structures such as flagella or...
n plastid, or
apicoplastAn apicoplast is a derived non-photosynthetic plastid found in most Apicomplexa, including malaria parasites such as Plasmodium falciparum, but not in others such as Cryptosporidium. It originated from an algae through secondary endosymbiosis...
, is an essential organelle, thought to be involved in the synthesis of lipids and several other compounds, and provides an attractive target for antimalarial drug development, particularly in light of the emergence of parasites resistant to chloroquine and other existing antimalarial agents.
Uncomplicated falciparum malaria
According to WHO guidelines 2010, artemisinin-based combination therapies (ACTs) are the recommended first line antimalarial treatments for uncomplicated malaria caused by
P. falciparum. The following ACTs are recommended by the WHO:
- artemether
Artemether is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. It is combined with Lumefantrine and sold by Novartis under the brand names Riamet and Co-Artem.-Chemical nature:...
plus lumefantrineLumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....
- artesunate
Artesunate is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection...
plus amodiaquineAmodiaquine is a 4-aminoquinoline compound related to chloroquine, used as an antimalarial and anti-inflammatory agent....
- artesunate plus mefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...
- artesunate plus sulfadoxine-pyrimethamine
- dihydroartemisinin
Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself...
plus piperaquinePiperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based...
The choice of ACT in a country or region will be based on the level of resistance to the constituents in the combination. Artemisinin and its derivatives should not be used as monotherapy in uncomplicated
falciparum malaria. As second-line antimalarial treatment, when initial treatment doesn’t work or stops working, it is recommended to use an alternative ACT known to be effective in the region, such as:
- Artesunate plus tetracycline or doxycycline or clindamycin.
- Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
plus tetracycline or doxycycline or clindamycin
Any of these combinations are to be given for 7 days.
For pregnant women, the recommended first-line treatment during the first trimester is quinine plus clindamycin for 7 days. Artesunate plus clindamycin for 7 days is indicated if this treatment fails. 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
complianceIn medicine, compliance describes the degree to which a patient correctly follows medical advice...
with a 7-day treatment. 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. Lactating women should receive standard antimalarial treatment (including ACTs) except for
dapsoneDapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
,
primaquinePrimaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...
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.
For travellers returning to non-endemic countries, any of the following is recommended:
- atovaquone
Atovaquone is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about US$2.13 per standard 250 mg. tablet...
-proguanilProguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...
- artemether-lumefantrine;
- quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
plus doxycyclineDoxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
or clindamycinClindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
.
Severe falciparum malaria
In severe
falciparum malaria, it is recommended that rapid clinical assessment and confirmation of the diagnosis is made, followed by administration of full doses of parenteral antimalarial treatment without delay with whichever effective antimalarial is first available.
For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended. Quinine is an acceptable alternative if parenteral artesunate is not available.
For children, especially in the malaria endemic areas of Africa, any the following antimalarial
medicines is recommended:
- artesunate IV or IM
- quinine (IV infusion or divided IM injection)
- artemether IM. It should only be used if none of the alternatives are available as its absorption may be erratic.
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. Thereafter, it is recommended to complete treatment by giving a complete course of any of the following:
- an ACT
- artesunate plus clindamycin or doxycycline
- quinine plus clindamycin or doxycycline
If complete treatment of severe malaria is not possible, it is recommended that patients are given pre-referral treatment and referred immediately to an appropriate facility for further treatment. The following are options for pre-referral treatment:
- rectal artesunate
- quinine IM
- artesunate IM
- artemether IM
History of falciparum treatment
Attempts to make synthetic antimalarials began in 1891.
AtabrineQuinacrine is a drug with a number of different medical applications. It is related to mefloquine.-Uses:Its main effects are as an antiprotozoal, antirheumatic and an intrapleural sclerosing agent....
, 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
chloroquineChloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
, which went into use in the North African campaigns.
Mao ZedongMao Zedong, also transliterated as Mao Tse-tung , and commonly referred to as Chairman Mao , was a Chinese Communist revolutionary, guerrilla warfare strategist, Marxist political philosopher, and leader of the Chinese Revolution...
encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War.
ArtemisininArtemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
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
culturedMalaria culture is the method to grow malaria parasites outside the body i.e. in an ex vivo environment.Plasmodium falciparum is currently the only human malaria parasite that has been successfully cultured continuously ex vivo...
in vitro for the first time which facilitated the development of new drugs substantially.
A 2008 study published in the
New England Journal of MedicineThe New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
highlighted the emergence of artemisinin-resistant strains of
P.falciparum in
CambodiaCambodia , officially known as the Kingdom of Cambodia, is a country located in the southern portion of the Indochina Peninsula in Southeast Asia...
.
Vaccination
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 systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
including immune suppression.
Dendritic cellDendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s suffer a maturation defect following interaction with infected erythrocytes and become unable to induce protective liver-stage
immunityImmunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
. Infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The
var gene products, a group of highly expressed surface
antigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s, bind the Fab and Fc fragments of human immunoglobulins in a fashion similar to protein A to
Staphylococcus aureusStaphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, 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
- Malaria Atlas Project
The Malaria Atlas Project, abbreviated as MAP, is a non-profit project primarily funded by the Wellcome Trust, UK. MAP is a joint project between the Malaria Public Health & Epidemiology Group, Centre for Geographic Medicine, Kenya and the Spatial Ecology & Epidemiology Group, University of...
- List of parasites (human)
- UCSC Malaria Genome Browser
UCSC Malaria Genome Browser is a bioinformatic research tool to study the malaria genome, developed by Hughes Undergraduate Research Laboratory together with the laboratory of Prof. Manuel Ares Jr. at the University of California, Santa Cruz....
Overview
Blood slides
Case histories
Pathology due to Plasmodium falciparum
Brain
Spleen
Liver
Kidney
Plasmodium falciparum genome data
Other