Plasmodium falciparum

Source: Wikipedia, the free encyclopedia.

Plasmodium falciparum
Macrogametocyte (left) and microgametocyte (right) of P. falciparum
Scientific classification Edit this classification
Domain: Eukaryota
Clade: Diaphoretickes
Clade: SAR
Clade: Alveolata
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemospororida
Family: Plasmodiidae
Genus: Plasmodium
Species:
P. falciparum
Binomial name
Plasmodium falciparum
(Welch, 1897)
Synonyms[1]
  • Oscillaria malariae Laveran, 1881
  • Plasmodium malariae Marchiafava and Celli, 1885
  • Laverania malariae Feletti and Grassi, 1890
  • Ematozoo falciforme Antolisei and Angelini, 1890
  • Haemamoeba immaculata Grassi, 1891
  • Haemamoeba laverani Labbe, 1894
  • Haematozoon falciforme Thayer and Hewetson, 1895
  • Haematozoon falciparum Welch, 1897
  • Haemosporidium sedecimanae Lewkowicz, 1897
  • Haemosporidium undecimanae Lewkowicz, 1897
  • Haemosporidium vigesimotertianae Lewkowicz, 1897

Plasmodium falciparum is a

Group 2A (probable) carcinogen
.

The species originated from the malarial parasite

Alphonse Laveran was the first to identify the parasite in 1880, and named it Oscillaria malariae. Ronald Ross discovered its transmission by mosquito in 1897. Giovanni Battista Grassi elucidated the complete transmission from a female anopheline mosquito to humans in 1898. In 1897, William H. Welch created the name Plasmodium falciparum, which ICZN formally adopted in 1954. P. falciparum assumes several different forms during its life cycle. The human-infective stage are sporozoites from the salivary gland of a mosquito. The sporozoites grow and multiply in the liver to become merozoites. These merozoites invade the erythrocytes (red blood cells) to form trophozoites, schizonts and gametocytes, during which the symptoms of malaria are produced. In the mosquito, the gametocytes undergo sexual reproduction to a zygote, which turns into ookinete. Ookinete forms oocytes
from which sporozoites are formed.

In 2022, some 249 million cases of malaria worldwide resulted in an estimated 608000 deaths, with 80 percent being 5 years old or less.[7] Nearly all malarial deaths are caused by P. falciparum, and 95% of such cases occur in Africa. In Sub-Saharan Africa, almost 100% of cases were due to P. falciparum, whereas in most other malarial countries, other, less virulent plasmodial species predominate.[8]

History

Laveran's drawing of various stages of P. falciparum as seen on fresh blood (1880).

Falciparum malaria was familiar to the ancient Greeks, who gave the general name πυρετός (pyretós) "fever".[9] Hippocrates (c. 460–370 BCE) gave several descriptions on tertian fever and quartan fever.[10] It was prevalent throughout the ancient Egyptian and Roman civilizations.[11] It was the Romans who named the disease "malaria"—mala for bad, and aria for air, as they believed that the disease was spread by contaminated air, or miasma.[10][12]

Discovery

A German physician,

French Academy of Medicine in Paris, and published it in The Lancet in 1881. He gave it the scientific name Oscillaria malariae.[12] However, his discovery was received with skepticism, mainly because by that time, leading physicians such as Theodor Albrecht Edwin Klebs and Corrado Tommasi-Crudeli claimed that they had discovered a bacterium (which they called Bacillus malariae) as the pathogen of malaria. Laveran's discovery was only widely accepted after five years when Camillo Golgi confirmed the parasite using better microscopes and staining techniques. Laveran was awarded the Nobel Prize in Physiology or Medicine in 1907 for his work. In 1900, the Italian zoologist Giovanni Battista Grassi categorized Plasmodium species based on the timing of fever in the patient; malignant tertian malaria was caused by Laverania malariae (now P. falciparum), benign tertian malaria by Haemamoeba vivax (now P. vivax), and quartan malaria by Haemamoeba malariae (now P. malariae).[13]

The British physician Patrick Manson formulated the mosquito-malaria theory in 1894; until that time, malarial parasites were believed to be spread in air as miasma, a Greek word for pollution.[12] His colleague Ronald Ross of the Indian Medical Service validated the theory while working in India. Ross discovered in 1897 that malarial parasites lived in certain mosquitoes. The next year, he demonstrated that a malarial parasite of birds could be transmitted by mosquitoes from one bird to another. Around the same time, Grassi demonstrated that P. falciparum was transmitted in humans only by female anopheline mosquito (in his case Anopheles claviger).[14] Ross, Manson and Grassi were nominated for the Nobel Prize in Physiology or Medicine in 1902. Under controversial circumstances, only Ross was selected for the award.[15]

There was a long debate on the taxonomy. It was only in 1954 the

William Henry Welch in 1897.[17] It is derived from the Latin falx, meaning "sickle" and parum meaning "like or equal to another".[16]

Origin and evolution

P. falciparum is now generally accepted to have evolved from

chimpanzee parasite P. reichenowi, which was previously thought to be the closest relative of P. falciparum. P. falciparum was also once thought to originate from a parasite of birds.[23]

Levels of genetic polymorphism are extremely low within the P. falciparum genome compared to that of closely related, ape infecting species of Plasmodium (including P. praefalciparum).[24][20] This suggests that the origin of P. falciparum in humans is recent, as a single P. praefalciparum strain became capable of infecting humans.[20] The genetic information of P. falciparum has signaled a recent expansion that coincides with the agricultural revolution. It is likely that the development of extensive agriculture increased mosquito population densities by giving rise to more breeding sites, which may have triggered the evolution and expansion of P. falciparum.[25]

Structure

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.
Ring forms in red blood cells (Giemsa stain)

P. falciparum does not have a fixed structure but undergoes continuous change during the course of its life cycle. A sporozoite is spindle-shaped and 10–15 μm long. In the liver it grows into an ovoid schizont of 30–70 μm in diameter. Each schizont produces merozoites, each of which is roughly 1.5 μm in length and 1 μm in diameter. In the erythrocyte the merozoite form a ring-like structure, becoming a trophozoite. A trophozoite feeds on the haemoglobin and forms a granular pigment called

haemozoin. Unlike those of other Plasmodium species, the gametocytes of P. falciparum are elongated and crescent-shaped, by which they are sometimes identified. A mature gametocyte is 8–12 μm long and 3–6 μm wide. The ookinete is also elongated measuring about 18–24 μm. An oocyst is rounded and can grow up to 80 μm in diameter.[26] Microscopic examination of a blood film reveals only early (ring-form) trophozoites and gametocytes that are in the peripheral blood. Mature trophozoites or schizonts in peripheral blood smears, as these are usually sequestered in the tissues. On occasion, faint, comma-shaped, red dots are seen on the erythrocyte surface. These dots are Maurer's cleft and are secretory organelles that produce proteins and enzymes essential for nutrient uptake and immune evasion processes.[27]

The apical complex, which is actually a combination of organelles, is an important structure. It contains secretory organelles called rhoptries and micronemes, which are vital for mobility, adhesion, host cell invasion, and parasitophorous vacuole formation.

MEP (non-mevalonate) pathway.[29]

Genome

In 1995 the Malaria Genome Project was set up to sequence the genome of P. falciparum. The genome of its

proteins are targeted to the apicoplast, while 4.7% of the proteome is targeted to the mitochondria.[31]

Life cycle

Anopheles mosquito, the carrier of Plasmodium falciparum
Anopheles mosquito, the carrier of Plasmodium falciparum

Humans are the intermediate hosts in which asexual reproduction occurs, and female anopheline mosquitos are the definitive hosts harbouring the sexual reproduction stage.[32]

In humans

Life cycle of Plasmodium

Infection in humans begins with the bite of an infected female Anopheles mosquito. Out of about 460 species of Anopheles mosquito, more than 70 species transmit falciparum malaria.[33] Anopheles gambiae is one of the best known and most prevalent vectors, particularly in Africa.[34]

The infective stage called the

plasma membrane.[37]

Liver stage or exo-erythrocytic schizogony

Entering the hepatocytes, the parasite loses its

apical complex and surface coat, and transforms into a trophozoite. Within the parasitophorous vacuole of the hepatocyte, it undergoes 13–14 rounds of mitosis which produce a syncytial cell (coenocyte) called a schizont. This process is called schizogony. A schizont contains tens of thousands of nuclei. From the surface of the schizont, tens of thousands of haploid (1n) daughter cells called merozoites emerge. The liver stage can produce up to 90,000 merozoites,[38] which are eventually released into the bloodstream in parasite-filled vesicles called merosomes.[39]

Blood stage or erythrocytic schizogony

erythrocyte.[40] 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.[41]

Within the erythrocyte, the parasite metabolism depends on the digestion of

haemoglobin. The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during the blood stage.[36]

The parasite can also alter the morphology of the erythrocyte, causing knobs on the erythrocyte membrane. 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 erythrocyte 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.[42]

Trophozoite

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. The trophozoite feeds on the haemoglobin of the erythrocyte, digesting its proteins and converting (by

crystals called haemozoin.[43][44] The young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing multiplication.[45]

Schizont

At the schizont stage, the parasite replicates its DNA multiple times and multiple mitotic divisions occur asynchronously.[46][47] Cell division and multiplication in the erythrocyte is called erythrocytic schizogony. Each schizont forms 16-18 merozoites.[45] The red blood cells are ruptured by the merozoites. The liberated merozoites invade fresh erythrocytes. A free merozoite is in the bloodstream for roughly 60 seconds before it enters another erythrocyte.[40]

The duration of one complete erythrocytic schizogony is approximately 48 hours. This gives rise to the characteristic clinical manifestations of falciparum malaria, such as fever and chills, corresponding to the synchronous rupture of the infected erythrocytes.[48]

Gametocyte

Some merozoites differentiate into sexual forms, male and female gametocytes. These gametocytes take roughly 7–15 days to reach full maturity, through the process called gametocytogenesis. These are then taken up by a female Anopheles mosquito during a blood meal.[49]

Incubation period

The time of appearance of the symptoms from infection (called incubation period) is shortest for P. falciparum among Plasmodium species. An average incubation period is 11 days,[48] but may range from 9 to 30 days. In isolated cases, prolonged incubation periods as long as 2, 3 or even 8 years have been recorded.[50] Pregnancy and co-infection with HIV are important conditions for delayed symptoms.[51] Parasites can be detected from blood samples by the 10th day after infection (pre-patent period).[48]

In mosquitoes

Within the mosquito midgut, the female gamete maturation process entails slight morphological changes, becoming more enlarged and spherical. The male gametocyte undergoes a rapid nuclear division within 15 minutes, producing eight

haemolymph. They migrate to the mosquito salivary glands where they undergo further development and become infective to humans.[36]

Meiosis

Plasmodium falciparum is haploid (one set of chromosomes) during its reproductive stages in human blood and liver. When a mosquito takes a blood meal from a plasmodium infected human host, this meal may include haploid microgametes and macrogametes. Such gametes can fuse within the mosquito to form a diploid (2N) plasmodium zygote, the only diploid stage in the life cycle of these parasites.[54] The zygote can undergo another round of chromosome replication to form a ookinete (4N) (see Figure: Life cycle of plasmodium). The ookinete that differentiates from the zygote is a highly mobile stage that invades the mosquito midgut. The ookinetes can undergo meiosis involving two meiotic divisions leading to the release of haploid sporozoites (see Figure).[54] The sporozoite is an elongated crescent shaped invasive stage. These sporozoites may migrate to the mosquito’s salivary glands and can enter a human host when the mosquito takes a blood meal. The sporozoite then can move to the human host liver and infect hepatocytes.

The profile of genes encoded by plasmodium that are employed in meiosis has some overlap with the profile of genes employed in meiosis in other more well studied organisms, but is more divergent and is lacking some components of the meiotic process found in other organisms.[54] During plasmodium meiosis, recombination occurs between homologous chromosomes as in other organisms.

Interaction with human immune system

Immune response

A single anopheline mosquito can transmit hundreds of P. falciparum sporozoites in a single bite under experimental conditions, but, in nature the number is generally less than 80.

macrophages.[57]

Only a small number (0.5-5%) of sporozoites enter the blood stream into the liver. In the liver, the activated CD8+ T cells from the lymph bind the sporozoites through the

natural killer cells.[59]

Immune system evasion

Although P. falciparum is easily recognized by the human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens.[60] The initial infective stage sporozoites produce circumsporozoite protein (CSP), which binds to hepatocytes.[61] Binding to and entering into the hepatocytes is aided by thrombospondin-related anonymous protein (TRAP).[62] TRAP and other secretory proteins (including sporozoite microneme protein essential for cell traversal 1, SPECT1 and SPECT2) from microneme allow the sporozoite to move through the blood, avoiding immune cells and penetrating hepatocytes.[63]

During erythrocyte invasion, merozoites release merozoite cap protein-1 (MCP1), apical membrane antigen 1 (AMA1), erythrocyte-binding antigens (EBA), myosin A tail domain interacting protein (MTIP), and

PfEMP1 is the most important, capable of acting as both an antigen and an adhesion molecule.[65]

Pathogenicity

Main article: Malaria

The clinical symptoms of falciparum malaria are produced by the rupture and destruction of erythrocytes by the merozoites. High fever, called paroxysm, is the most basic indication. The fever has a characteristic cycle of hot stage, cold stage and sweating stages.

dry cough are also generally associated. High heartrate, jaundice, pallor, orthostatic hypotension, enlarged liver, and enlarged spleen are also diagnosed.[48]

The insoluble β-hematin crystals, haemozoin, produced from digestion of haemoglobin of the RBCs is the main agent that affect body organs. Acting as a blood toxin, haemozoin-containing RBCs cannot be attacked by phagocytes during immune response to malaria.

inflammatory reaction that results in increased fever.[70][71] It is the haemozoin that is deposited in body organs such as the spleen and liver, as well as in kidneys and lungs, to cause their enlargement and discolouration.[72][73] Because of this, haemozoin is also known as malarial pigment.[74][75]

Unlike other malarias, which show regular periodicity of fever, falciparum, though exhibiting a 48-hour cycle, usually presents as irregular bouts of fever. This difference is due the ability of P. falciparum merozoites to invade a large number of RBCs sequentially without coordinated intervals, which is not seen in other malarial parasites.

antigens that appear on infected erythrocytes.[77] But increased immunity in the mother increases susceptibility to malaria in newborn babies.[76]

P. falciparum works via sequestration, a process by which group of infected RBCs are clustered, which is not exhibited by any other species of malarial parasites.

cerebral malaria.[79]

Cerebral malaria is the most dangerous condition of any malarial infection and the most severe form of

neurological disorders. According to the WHO definition, the clinical symptom is indicated by coma and diagnosis by high level of merozoites in the peripheral blood samples.[80][81] It is the deadliest form of malaria, and to it are attributed to 0.2 million to over a million annual deaths throughout the ages. Most deaths are of children of below 5 years of age.[82][83] It occurs when the merozoites invade the brain and causes brain damage of varying degrees. Death is caused by oxygen deprivation (hypoxia) due to inflammatory cytokine production and vascular leakage induced by the merozoites.[84] Among the surviving individuals, persistent medical conditions such as neurological impairment, intellectual disability, and behavioural problems exist. Among them, epilepsy is the most common condition, and cerebral malaria is the leading cause of acquired epilepsy among African children.[85]

The reappearance of falciparum symptom, a phenomenon called recrudescence, is often seen in survivors.[86] Recrudescence can occur even after successful antimalarial medication.[87][88] It may take a few months or even several years. In some individuals, it takes as along as three years.[89] In isolated cases, the duration can reach or exceed 10 years.[90][91] It is also a common incident among pregnant women.[92][93]

Distribution and epidemiology

Relative incidence of Plasmodium species by country of origin for imported cases to non-endemic countries, showing P. falciparum (red) predominating in areas including Africa and the Caribbean.[94]
The Z(T) normalized index of temperature suitability for P. falciparum displayed by week across an average year.

P. falciparum is endemic in 84 countries,[95] and is found in all continents except Europe. Historically, it was present in most European countries, but improved health conditions led to the disappearance in the early 20th century.[96] The only European country where it used to be historically prevalent, and from where we got the name malaria, Italy had been declared malaria-eradicated country. In 1947, the Italian government launched the National Malaria Eradication Program, and following, an anti-mosquito campaign was implemented using DDT.[97] The WHO declared Italy free of malaria in 1970.[98]

There were 247 million cases of malaria worldwide in 2021, resulting in an estimated 619,000 deaths.[95] The infection is most prevalent in Africa, where 94% of malaria deaths occur. Children under five years of age are most affected, and 67% of malaria deaths occurred in this age group. 80% of the infection is found in Sub-Saharan Africa, 7% in the South-East Asia, and 2% in the Eastern Mediterranean. Nigeria has the highest incidence, with 27% of the total global cases. Outside Africa, India has the highest incidence, with 4.5% of the global burden. Europe is regarded as a malaria-free region. Historically, the parasite and its disease had been most well known in Europe. But medical programmes since the early 20th century, such as insecticide spraying, drug therapy and environmental engineering, resulted in complete eradication in the 1970s.[99] It is estimated that approximately 2.4 billion people are at constant risk of infection.[100]

Treatment

Main article: Antimalarial medication

History

See also: History of malaria

In 1640, Huan del Vego first employed the

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.[101][102] The total synthesis of quinine was achieved by American chemists R.B. Woodward and W.E. Doering in 1944. Woodward received the Nobel Prize in Chemistry in 1965.[103]

Attempts to make synthetic antimalarials began in 1891.

Atabrine, developed in 1933, was used widely throughout the Pacific in World War II, but was unpopular because of its adverse effects.[104] In the late 1930s, the Germans developed chloroquine, which went into use in the North African campaigns. Creating a secret military project called Project 523, Mao Zedong encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. Tu Youyou discovered artemisinin in the 1970s from sweet wormwood (Artemisia annua). This drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment. Tu won the Nobel Prize in Physiology or Medicine in 2015.[105]

Uncomplicated malaria

According to WHO guidelines 2010,

dihydroartemisinin/piperaquine.[106]

The choice of ACT is based on the level of resistance to the constituents in the combination. Artemisinin and its derivatives are not appropriate for monotherapy. As second-line antimalarial treatment, when initial treatment does not work, an alternative ACT known to be effective in the region is recommended, such as artesunate plus tetracycline or

first trimester is quinine plus clindamycin for 7 days.[106] Artesunate plus clindamycin for 7 days is indicated if this treatment fails. For travellers returning to nonendemic countries, atovaquone/proguanil, artemether/lumefantrineany and quinine plus doxycycline or clindamycin are recommended.[106]

Severe malaria

For adults,

intramuscular (IM) artesunate is recommended.[106] Quinine is an acceptable alternative if parenteral artesunate is not available.[106]

For children, especially in the malaria-endemic areas of Africa, artesunate IV or IM, quinine (IV infusion or divided IM injection), and artemether IM are recommended.[106]

Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient's ability to tolerate oral medication earlier.[106] Thereafter, complete treatment is recommended including complete course of ACT or quinine plus clindamycin or doxycycline.[106]

Vaccination

Main article: Malaria vaccine

RTS,S is the only candidate as malaria vaccine to have gone through clinical trials.[107] Analysis of the results of the phase III trial (conducted between 2011 and 2016) revealed a rather low efficacy (20-39% depending on age, with up to 50% in 5–17-month aged babies), indicating that the vaccine will not lead to full protection and eradication.[108]

On October 6, 2021, the World Health Organization recommended malaria vaccination for children at risk.[109]

Cancer

The

Group 1 carcinogen.[111]

In 1989, it was realised that EBV requires other infections such as with malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt's lymphoma decreased with effective treatment of malaria over several years.

double-strand break) of an EBV-infected lymphocytes. The damaged DNA undergoes uncontrolled replication, thus making the cell cancerous.[116]

Influence on the human genome

Further information:
Genetic resistance to malaria

The high

thalassaemia might provide similar protection.[120] This hypothesis has since been confirmed and extended to hemoglobin E[121] and hemoglobin C.[122]

See also

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Further reading

External links

Scholia has a topic profile for Plasmodium falciparum.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Plasmodium_falciparum&oldid=1201008978"