Plasmodium falciparum: Difference between revisions

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''Haemosporidium undecimanae'' <small>Lewkowicz, 1897</small><br />
''Haemosporidium undecimanae'' <small>Lewkowicz, 1897</small><br />
''Haemosporidium vigesimotertianae'' <small>Lewkowicz, 1897</small>
''Haemosporidium vigesimotertianae'' <small>Lewkowicz, 1897</small>
| synonyms_ref = <ref>{{cite book|authors=Coatney GR, Collins WE, Warren M, Contacos PG|year=1971|title=The primate malarias|publisher=Division of Parasitic Disease, CDC|chapter=22 ''Plasmodium falciparum'' (Welch, 1897)|pages=263|url=http://stacks.cdc.gov/view/cdc/6538}}</ref>
| synonyms_ref = <ref>{{cite book|vauthors=Coatney GR, Collins WE, Warren M, Contacos PG|year=1971|title=The primate malarias|publisher=Division of Parasitic Disease, CDC|chapter=22 ''Plasmodium falciparum'' (Welch, 1897)|pages=263|url=http://stacks.cdc.gov/view/cdc/6538}}</ref>
}}
}}


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== Influence on the human genome ==
== Influence on the human genome ==
{{further information|Genetic resistance to malaria}}
{{further information|Genetic resistance to malaria}}
The presence of ''P. falciparum'' in human populations has exerted [[selective pressure]] on the human genome. E. A. Beet, a doctor working in [[Southern Rhodesia]] (now [[Zimbabwe]]) had observed in 1948 that [[sickle-cell disease]] was related to lower rate of malaria infection.<ref>{{cite journal|last1=Beet|first1=EA|title=Sickle cell disease in the Balovale District of Northern Rhodesia|journal=East African Medical Journal|date=1946|volume=23|pages=75–86|pmid=21027890}}</ref> This suggestion was reiterated by [[J. B. S. Haldane]] in 1948, who suggested that [[thalassaemia]] could provide similar protection.<ref>{{cite journal|last1=Hedrick|first1=P W|title=Population genetics of malaria resistance in humans|journal=Heredity|date=2011|volume=107|issue=4|pages=283–304|doi=10.1038/hdy.2011.16|pmid=21427751|pmc=3182497}}</ref> This hypothesis has since been confirmed and extended to [[hemoglobin E]],<ref>{{cite journal|last1=Chotivanich|first1=K|last2=Udomsangpetch|first2=R|last3=Pattanapanyasat|first3=K|last4=Chierakul|first4=W|last5=Simpson|first5=J|last6=Looareesuwan|first6=S|last7=White|first7=N|title=Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria.|journal=Blood|date=2002|volume=100|issue=4|pages=1172–6|pmid=12149194}}</ref> [[hemoglobin C]] and Hemoglobin S.<ref>{{cite journal|last1=Verra|first1=Federica|last2=Simpore|first2=Jacques|last3=Warimwe|first3=George M.|last4=Tetteh|first4=Kevin K.|last5=Howard|first5=Tevis|last6=Osier|first6=Faith H. A.|last7=Bancone|first7=Germana|last8=Avellino|first8=Pamela|last9=Blot|first9=Isa|last10=Fegan|first10=Greg|last11=Bull|first11=Peter C.|last12=Williams|first12=Thomas N.|last13=Conway|first13=David J.|last14=Marsh|first14=Kevin|last15=Modiano|first15=David|last16=Hall|first16=Neil|title=Haemoglobin C and S Role in Acquired Immunity against Plasmodium falciparum Malaria|journal=PLoS ONE|date=3 October 2007|volume=2|issue=10|pages=e978|doi=10.1371/journal.pone.0000978|pmid=17912355|pmc=1991593|display-authors=8}}</ref>
The high [[death|mortality]] and [[morbidity]] caused by ''P.&nbsp;falciparum'' has placed the greatest [[Selection (biology)|selective pressure]] on the [[human genome]] in recent history. Several genetic factors provide [[genetic resistance to malaria|some resistance to ''Plasmodium'' infection]], including [[sickle cell trait]], [[thalassaemia]] traits, [[glucose-6-phosphate dehydrogenase deficiency]], and the absence of [[Duffy antigen]]s on red blood cells.<ref name="Kwiatkowski 2005">{{Cite journal |author=Kwiatkowski DP |title=How malaria has affected the human genome and what human genetics can teach us about malaria |journal=American Journal of Human Genetics |volume=77 |issue=2 |pages=171–92 |year=2005 |pmid=16001361 |pmc=1224522 |doi=10.1086/432519}} {{open access}}</ref><ref name="Hedrick 2011">{{Cite journal |author=Hedrick PW |title=Population genetics of malaria resistance in humans |journal=Heredity |year=2011 |volume=107 |issue=4 |pages=283–304 |pmid=21427751 |doi=10.1038/hdy.2011.16 |pmc=3182497}} {{open access}}</ref> The presence of ''P. falciparum'' in human populations has exerted [[selective pressure]] on the human genome. E. A. Beet, a doctor working in [[Southern Rhodesia]] (now [[Zimbabwe]]) had observed in 1948 that [[sickle-cell disease]] was related to lower rate of malaria infection.<ref>{{cite journal|last1=Beet|first1=EA|title=Sickle cell disease in the Balovale District of Northern Rhodesia|journal=East African Medical Journal|date=1946|volume=23|pages=75–86|pmid=21027890}}</ref> This suggestion was reiterated by [[J. B. S. Haldane]] in 1948, who suggested that [[thalassaemia]] could provide similar protection.<ref>{{cite journal|last1=Hedrick|first1=P W|title=Population genetics of malaria resistance in humans|journal=Heredity|date=2011|volume=107|issue=4|pages=283–304|doi=10.1038/hdy.2011.16|pmid=21427751|pmc=3182497}}</ref> This hypothesis has since been confirmed and extended to [[hemoglobin E]],<ref>{{cite journal|last1=Chotivanich|first1=K|last2=Udomsangpetch|first2=R|last3=Pattanapanyasat|first3=K|last4=Chierakul|first4=W|last5=Simpson|first5=J|last6=Looareesuwan|first6=S|last7=White|first7=N|title=Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria.|journal=Blood|date=2002|volume=100|issue=4|pages=1172–6|pmid=12149194}}</ref> [[hemoglobin C]] and Hemoglobin S.<ref>{{cite journal|last1=Verra|first1=Federica|last2=Simpore|first2=Jacques|last3=Warimwe|first3=George M.|last4=Tetteh|first4=Kevin K.|last5=Howard|first5=Tevis|last6=Osier|first6=Faith H. A.|last7=Bancone|first7=Germana|last8=Avellino|first8=Pamela|last9=Blot|first9=Isa|last10=Fegan|first10=Greg|last11=Bull|first11=Peter C.|last12=Williams|first12=Thomas N.|last13=Conway|first13=David J.|last14=Marsh|first14=Kevin|last15=Modiano|first15=David|last16=Hall|first16=Neil|title=Haemoglobin C and S Role in Acquired Immunity against Plasmodium falciparum Malaria|journal=PLoS ONE|date=3 October 2007|volume=2|issue=10|pages=e978|doi=10.1371/journal.pone.0000978|pmid=17912355|pmc=1991593|display-authors=8}}</ref>


== Origin and evolution ==
== Origin and evolution ==

The closest relative of ''P. falciparum'' is ''P. praefalciparum'', a parasite of [[gorilla]]s, as supported by [[mitochondrial DNA|mitochondrial]], [[apicoplast]]ic and [[nuclear DNA|nuclear]] DNA sequences.<ref name="Liu et al. 2010">{{Cite journal| volume = 467| last1 = Liu| first1 = W| author2 = Y Li, GH Learn, RS Rudicell, JD Robertson, BF Keele, JN Ndjango, CM Sanz, DB Morgan, S Locatelli, MK Gonder, PJ Kranzusch, PD Walsh, E Delaporte, E Mpoudi-Ngole, AV Georgiev, MN Muller, GM Shaw, M Peeters, PM Sharp, JC Rayner, BH Hahn| title = Origin of the human malaria parasite ''Plasmodium falciparum'' in gorillas| journal = Nature| year = 2010| doi = 10.1038/nature09442| issue=7314|bibcode = 2010Natur.467..420L| pmid=20864995
The closest relative of ''P. falciparum'' is ''P. praefalciparum'', a parasite of [[gorilla]]s, as supported by [[mitochondrial DNA|mitochondrial]], [[apicoplast]]ic and [[nuclear DNA|nuclear]] DNA sequences.<ref name="Liu et al. 2010">{{Cite journal| volume = 467| last1 = Liu| first1 = W| author2 = Y Li, GH Learn, RS Rudicell, JD Robertson, BF Keele, JN Ndjango, CM Sanz, DB Morgan, S Locatelli, MK Gonder, PJ Kranzusch, PD Walsh, E Delaporte, E Mpoudi-Ngole, AV Georgiev, MN Muller, GM Shaw, M Peeters, PM Sharp, JC Rayner, BH Hahn| title = Origin of the human malaria parasite ''Plasmodium falciparum'' in gorillas| journal = Nature| year = 2010| doi = 10.1038/nature09442| issue=7314|bibcode = 2010Natur.467..420L| pmid=20864995
| pmc=2997044| pages = 420–5}}</ref><ref name="Duval et al. 2010">{{Cite journal| volume = 107| last1 = Duval
| pmc=2997044| pages = 420–5}}</ref><ref name="Duval et al. 2010">{{Cite journal| volume = 107| last1 = Duval
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Levels of genetic [[Polymorphism (biology)|polymorphism]] are extremely low within the ''P. falciparum'' genome compared to that of closely related, ape infecting species of ''Plasmodium'' (including ''P. praefalciparum'')<ref name="Hartl 2004">{{Cite journal| volume = 2| issue = 1| pages = 15–22| last = Hartl| first = DH| title = The origin of malaria: mixed messages from genetic diversity| journal = Nature Reviews Microbiology| date = January 2004
Levels of genetic [[Polymorphism (biology)|polymorphism]] are extremely low within the ''P. falciparum'' genome compared to that of closely related, ape infecting species of ''Plasmodium'' (including ''P. praefalciparum'')<ref name="Hartl 2004">{{Cite journal| volume = 2| issue = 1| pages = 15–22| last = Hartl| first = DH| title = The origin of malaria: mixed messages from genetic diversity| journal = Nature Reviews Microbiology| date = January 2004
| pmid=15035005| doi = 10.1038/nrmicro795}}</ref><ref name="Liu et al. 2010" />''.'' This suggests that the origin of ''P. falciparum'' in humans is recent, as a single ''P. praefalciparum'' strain became capable of infecting humans.<ref name="Liu et al. 2010" />
| pmid=15035005| doi = 10.1038/nrmicro795}}</ref><ref name="Liu et al. 2010" />''.'' This suggests that the origin of ''P. falciparum'' in humans is recent, as a single ''P. praefalciparum'' strain became capable of infecting humans.<ref name="Liu et al. 2010" /> The genetic information of ''Plasmodium 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 ''Plasmodium falciparum''.<ref>{{cite journal | last1 = Hume | first1 = J.C. | last2 = Lyons | first2 = E.J. | last3 = Day | first3 = K.P. | year = 2003 | title = Human migration, mosquitoes and the evolution of ''Plasmodium falciparum'' | url = | journal = Trends Parasitol | volume = 19 | issue = 3| pages = 144–9 | doi=10.1016/s1471-4922(03)00008-4| pmid = 12643998 }}</ref>


==Distribution and epidemiology==
==Distribution and epidemiology==

Revision as of 05:09, 9 March 2018

Plasmodium falciparum
Blood smear of Plasmodium falciparum (gametocytes - sexual forms)
Scientific classification
Domain:
Eukaryota
(unranked):
SAR
(unranked):
Alveolata
Phylum:
Apicomplexa
Class:
Aconoidasida
Order:
Haemosporida
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 unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that cause malaria in humans.[2] It is transmitted through the bite of a female Anopheles mosquito. It is responsible for roughly 50% of all malaria cases.[3] It causes the disease's most dangerous form called falciparum malaria.[4][5] It is therefore regarded as the deadliest parasite in humans, causing a conservative estimate of one million deaths every year.[6]

The species originated from the malarial parasite Laverania found in gorillas, around 10,000 years ago. 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 is sporozoites from the salivary gland of a mosquito. The sporozoites grow and multiply in the liver to become merozoites. These merozites invade the erythrocytes (RBCs) 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 oocyts from which sporozoites are formed.

According to the World Health Organization report of 2015, there were 214 million cases of malaria worldwide. This resulted in an estimated 438,000 deaths.[7] Rates of infection decreased from 2000 to 2015 by 37%,[7] but increased from 2014's 198 million cases.[8] In Sub-Saharan Africa, over 75% of cases were due to P. falciparum, whereas in most other malarial countries, other, less virulent plasmodial species predominate. Almost every malarial death is caused by P. falciparum.[9]

History

P. falciparum is now generally accepted to have evolved from Laverania (a subgenus of Plasmodium found in apes) species present in gorilla in Western Africa.[10][11] Genetic diversity indicates that the human protozoan emerged around 10,000 years ago.[12] Falciparum malaria was familiar to Ancient Greeks, who gave the general name pyretos (meaning fever).[13] Hippocrates (c. 460-370 BCE) gave several descriptions on tertian fever and quartan fever.[14]

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

The French Army physician Charles Louis Alphonse Laveran correctly identified the parasite as a causative pathogen of malaria in 1880 and gave it the scientific name Oscillaria malariae.[15] He won 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).[16] 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).[15] His colleague Ronald Ross, a British Army surgeon, traveled to India to prove the theory. Ross discovered in 1897 that malarial parasite 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).[17] Under controversial circumstances, only Ronald Ross received the Nobel Prize in Physiology or Medicine in 1907.[18]

There was a long debate on the taxonomy. It was only in 1954 the International Commission on Zoological Nomenclature officially approved the binominal Plasmodium falciparum.[19] The valid genus Plasmodium was created by two Italian physicians Ettore Marchiafava and Angelo Celli in 1885. The species name was introduced by an American physician William Henry Welch in 1897.[20] It is derived from the Latin falx, meaning "sickle" and parum meaning "like or equal to another".[19]

Life cycle

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

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.[21] Anopheles gambiae is one of the best known and most prevalent vectors, particularly in Africa.[22]

The infective stage called sporozoites released from the salivary glands through the proboscis of the mosquito enter the bloodstream during feeding. The mosquito saliva contains antihemostatic and anti-inflammatory enzymes that disrupt blood clotting and inhibit the pain reaction. Typically, each infected bite contains 20-200 sporozoites.[23] The immune system clears the sporozoites from the circulation within 30 minutes. But a few escape and quickly invade liver cells (hepatocytes).[24]

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 and meiosis 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,[25] which are eventually released into the bloodstream in parasite-filled vesicles called merosomes.[26]

Blood stage or erythrocytic schizogony

Merozoites use the apicomplexan invasion organelles (apical complex, pellicle and surface coat) to recognize and enter the host erythrocyte (red blood cell). 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. The parasite forms a parasitophorous vesicle, to allow for its development inside the erythrocyte.[27] 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.[28]

Within the erythrocyte, the parasite metabolism depends on the digestion of hemoglobin. The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during the blood stage.[24]

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.

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 young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing schizogony.[29]

Schizont

At the schizont stage, the parasite replicates its DNA multiple times and multiple mitotic divisions occur asynchronously.[30][31] Each schizont forms 16-18 merozoites.[29] 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.[27]

The duration of each blood stage 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.[32]

Gametocyte

Not all of the merozoites divide into schizonts; some 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 gametocytes are taken up by a female Anopheles mosquito during a blood meal.[33]

Incubation period

The time of appearance of the symptoms from infection (called incubation period) in P. falciparum infection is 11 days, but may range from 11 to 14 days. Parasites can be detected from blood samples by the 10th day after infection (pre-patent period).[32]

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 flagellated microgametes by a process called exflagellation.[34] The flagellated microgamete fertilizes the female macrogamete to produce a diploid cell called a zygote. The zygote then develops into an ookinete. The ookinete is a motile cell, capable of invading other organs of the mosquito. It traverses the peritrophic membrane of the mosquito midgut and crosses the midgut epithelium. Once through the epithelium, the ookinete enters the basal lamina, and settles to an immotile oocyst. For several days, the oocyst undergoes 10 to 11 rounds of cell division to create a syncytial cell (sporoblast) containing thousands of nuclei. Meiosis takes place inside the sporoblast to produce over 3,000 haploid daughter cells called sporozoites on the surface of the mother cell.[35] Immature sporozoites break through the oocyst wall into the haemolymph. They migrate to the mosquito salivary glands where they undergo further development and become infective to humans.[24]

Pathogenesis

Main article: Malaria

The clinical symptoms of falciparum malaria are produced by the rupture of schizont and destruction of erythrocytes. Most of the patients experience fever (>92% of cases), chills (79%), headaches (70%), and sweating (64%). Dizziness, malaise, muscle pain, abdominal pain, nausea, vomiting, mild diarrhea, and dry cough are also generally associated. High heartrate, jaundice, pallor, orthostatic hypotension, enlarged liver, and enlarged spleen are also diagnosed.[32]

P. falciparum works via sequestration, a distinctive property not shared by any other Plasmodium. The mature schizonts change the surface properties of infected erythrocytes, causing them to stick to blood vessel walls (cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, such as the brain in cerebral malaria.[36]

P. falciparum is responsible for (almost) all severe and deaths due to malaria, in a condition called complicated or severe malaria. Complicated malaria occurs more commonly in children under age 5,[32] and sometimes in pregnant women (a condition specifically called pregnancy-associated malaria).[37] Women become susceptible to severe malaria during their first pregnancy. Susceptibility to severe malaria is reduced in subsequent pregnancies due to increased antibody levels against variant surface antigens that appear on infected erythrocytes.[38] But increased immunity in mother increases susceptibility to malaria in newborn babies.[37]

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.

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 trophozoites feed 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.[39] 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.[40]

An important cell organelle is apical complex, which is actually a combination of organelles. It contains secretory organelles called rhoptries and micronemes, which are vital for mobility, adhesion, host cell invasion, and parasitophorous vacuole formation.[23] As an apicomplexan, it harbours 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. The apicoplast is involved in the synthesis of lipids and several other compounds and provides an attractive drug target. During the asexual blood stage of infection, an essential function of the apicoplast is to produce the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the MEP (non-mevalonate) pathway .[41]

Genome

In 1995 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,[42] 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 was reported on 3 October 2002.[43] The roughly 24-megabase genome is extremely AT-rich (about 80%) and is organised into 14 chromosomes. Just over 5,300 genes were described. 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. It is estimated that 551, or roughly 10%, of the predicted nuclear-encoded proteins are targeted to the apicoplast, while 4.7% of the proteome is targeted to the mitochondria.[43]

Human immune system evasion

Although P. falciparum is easily recognized by human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens[44] The initial infective stage sporozoites produce circumsporozoite protein (CS), which binds to hepatocytes.[45] Binding to and entry into the hepatocytes is aided by another protein, thrombospondin-related anonymous protein (TRAP).[46] 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.[6]

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 merozoite surface proteins (MSPs).[44] Of these MSPs, MSP1 and MSP2 are primarily responsible for avoiding immune cells.[47] The virulence of P. falciparum is mediated by erythrocyte membrane proteins, which are produced by the schizonts and trophozoites inside the erythrocytes and are displayed on the erythrocyte membrane. PfEMP1 is the most important, capable of acting as both an antigen and an adhesion molecule.[48]

Influence on the human genome

Further information: Genetic resistance to malaria

The high mortality and morbidity caused by P. falciparum has placed the greatest selective pressure on the human genome in recent history. Several genetic factors provide some resistance to Plasmodium infection, including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens on red blood cells.[49][50] The presence of P. falciparum in human populations has exerted selective pressure on the human genome. E. A. Beet, a doctor working in Southern Rhodesia (now Zimbabwe) had observed in 1948 that sickle-cell disease was related to lower rate of malaria infection.[51] This suggestion was reiterated by J. B. S. Haldane in 1948, who suggested that thalassaemia could provide similar protection.[52] This hypothesis has since been confirmed and extended to hemoglobin E,[53] hemoglobin C and Hemoglobin S.[54]

Origin and evolution

The closest relative of P. falciparum is P. praefalciparum, a parasite of gorillas, as supported by mitochondrial, apicoplastic and nuclear DNA sequences.[55][56][57] These two species are closely related to the 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.[58]

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)[59][55]. This suggests that the origin of P. falciparum in humans is recent, as a single P. praefalciparum strain became capable of infecting humans.[55] The genetic information of Plasmodium 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 Plasmodium falciparum.[60]

Distribution and epidemiology

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

P. falciparum is found in all continents except Europe. Falciparum malaria affected 212 million people in 2015, and is most prevalent in Africa. According to a WHO report, 90% of the total global infection is in Africa, 7% in the South-East Asia, and 2% in the Eastern Mediterranean.[61] Europe is regarded as a malaria-free region. Historically, the parasite and its disease had been most well known in Europe. But medical programmes, such as insecticide spraying, drug therapy and environmental engineering since the early 20th century resulted in complete eradication in the 1970s.[62] It is estimated that approximately 2.4 billion people are at constant risk of infection.[63]

Treatment

Main article: Antimalarial medication

History

See also: History of malaria

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 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.[64][65] 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.[66]

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 adeverse effects.[67] 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.[68]

Uncomplicated malaria

According to WHO guidelines 2010,[69] artemisinin-based combination therapies (ACTs) are the recommended first-line antimalarial treatments for uncomplicated malaria caused by P. falciparum. WHO recommends combinations such as artemether/lumefantrine, artesunate/amodiaquine, artesunate/mefloquine, artesunate/sulfadoxine-pyrimethamine, and dihydroartemisinin/piperaquine.[69]

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 doxycycline or clindamycin, and quinine plus tetracycline or doxycycline or clindamycin. Any of these combinations is 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.[69] 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.[69]

Severe malaria

For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended.[69] Quinine is an acceptable alternative if parenteral artesunate is not available.[69]

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.[69]

Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient's ability to tolerate oral medication earlier.[69] Thereafter, complete treatment is recommended including complete course of ACT or quinine plus clindamycin or doxycycline.[69]

Vaccination

Main article: Malaria vaccine

RTS,S is the only candidate as malaria vaccine to have gone through clinical trials.[70] Analysis of the results of the phase III trial (conducted between 2011 and 2016) revealed a rather low efficacy (19-39% depending on age), indicating that the vaccine will not lead to full protection and eradication.[71]

See also

References

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Further reading

External links

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