Plasmodium falciparum biology

Plasmodium falciparum biology

Taxobox
color = khaki
name = "Plasmodium falciparum"



image_width = 240px
image_caption = Blood smear of "Plasmodium falciparum"
regnum = Protista
phylum = Apicomplexa
classis = Aconoidasida
ordo = Haemosporida
familia = Plasmodiidae
genus = "Plasmodium"
species = "P. falciparum"
binomial = "Plasmodium falciparum"
binomial_authority = Welch, 1897

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

Life Cycle

"Plasmodium falciparum" has a complicated life-cycle, requiring both a human and a mosquito host, and differentiating multiple times during its transmission/infection process.cite journal
last = Wirth
first = Dyann
authorlink =
coauthors =
title = The parasite genome: Biological revelations
journal = Nature
volume = 419
issue =
pages = 495–496
publisher =
location =
date = 3 October 2002
url = http://www.nature.com/nature/journal/v419/n6906/full/419495a.html
doi =
id =
accessdate =
]


frame|center|Plasmodium life cycle">cite web
last =
first =
authorlink =
coauthors =
title = DPDx - Malaria Image Library
work =
publisher =
date =
url = http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/Malaria_il.htm
format =
doi =
accessdate =
]

Human infection

"P. falciparum" is transmitted to humans by the females of the "Anopheles" species of mosquito. There are about 460 species of "Anopheles" mosquito, but only 68 transmit malaria. "Anopheles gambiae" is one of the best malaria vectors since it is long-lived, prefers feeding on humans, and lives in areas near human habitation. "A. gambiae" is found in Africa. cite web
last =
first =
authorlink =
coauthors =
title = Malaria eModule - Transmission
work =
publisher =
date =
url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_3.html
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Prior to transmission, "Plasmodium falciparum" resides within the salivary glad of the mosquito. The parasite is in its sporozoite stage at this point. As the mosquito takes its blood meal, it injects a small amount of saliva into the skin wound. The saliva contains antihemostatic and anti-inflammatory enzymes that disrupt the clotting process and inhibit the pain reaction.cite web
last =
first =
authorlink =
coauthors =
title = Malaria Site: Anopheles Mosquito
work =
publisher =
date =
url = http://www.malariasite.com/malaria/AnophelesMosquito.htm
format =
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] Typically, each infected bite contains 5-200 sporozoites which proceed to infect the human vector. Once in the human bloodstream, the sporozoites only circulate for a matter of minutes before infecting liver cells.

Liver stage

After circulating in the bloodstream, the "P. falciparum" sporozoites enter hepatocytes. At this point, the parasite loses its apical complex and surface coat, and transforms into a trophozoite. Within the parasitophorous vacuole of the hepatocyte, "P. falciparum" undergoes schizogonic development. In this stage, nucleus divides multiple times with a concomitant increase in cell size, but without cell segmentation. This exoerythrocytic schizogony stage of "P. falciparum" has a minimum duration of roughly 5.5 days. After segmentation, the parasite cells are differentiated into merozoites.cite web
last =
first =
authorlink =
coauthors =
title = Malaria eModule - Exo-Erythrocytic Stages
work =
publisher =
date =
url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_4.html
format =
doi =
accessdate =
]

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

Erythrocytic stage

"Merozoite"

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

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

"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 in the red blood cell cytoplasm. The young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing schizogonic division. cite web
last =
first =
authorlink =
coauthors =
title = Malaria eModule - ASEXUAL ERYTHROCYTIC STAGES
work =
publisher =
date =
url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5.html
format =
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]

"Schizont"

At the schizont stage, the parasite replicates its DNA multiple times without cellular segmentation. These schizonts then undergo cellular segmentation and differentiation to form roughly 16-18 merozoite cells in the erythrocyte. The merozoites burst from the red blood cell, and proceed to infect other erythrocytes. The parasite is in the bloodstream for roughly 60 seconds before it has entered another erythrocyte.cite journal
last = Cowman
first =
authorlink =
coauthors =
title = Invasion of Red Blood Cells by Malaria Parasites
journal = Cell
volume = 124
issue =
pages = 755–766
publisher =
location =
date = 24 February 2006
doi =
id =
accessdate =
]

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.cite web
last =
first =
authorlink =
coauthors =
title = Malaria eModule - SYNCHRONICITY
work =
publisher =
date =
url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_5_2.html
format =
doi =
accessdate =
] Specifically, human body temperature changes, as a result of the circadian rhythm, seem to play a role in the development of "P. falciparum" within the erythrocytic stage.

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

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

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

Gametocyte differentiation

During the erythrocytic stage, some merozoites develop into male and female gametocytes. This process is called gametocytogenesis.cite web
last =
first =
authorlink =
coauthors =
title = Malaria eModule - GAMETOCYTOGENESIS
work =
publisher =
date =
url = http://www.impact-malaria.com/FR/EPS/Formations_et_cours_internationaux/Formation_de_la_Liverpool_School_LSTMH/cours_liverpool/Unit_1/1_6_1.html
format =
doi =
accessdate =
] The specific factors and causes underlying this sexual differentiation are largely unknown. These gametocytes take roughly 8-10 days to reach full maturity. Note that the gametocytes remain within the erythrocytes until taken up by the mosquito host.

Mosquito stage

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

"Gametogenesis"

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

Gametogenesis has been shown to be caused by: 1) a sudden drop in temperature upon leaving the human host, 2) a rise in pH within the mosquito, and 3) xanthurenic acid within the mosquito.cite journal
last = Billker
first =
authorlink =
coauthors =
title = Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito
journal = Nature
volume = 392
issue =
pages = 289–292
publisher =
location =
date = March 19, 1998
doi =
id =
accessdate =
]

"Fertilization"

Fertilization of the female gamete by the male gamete occurs rapidly after gametogenesis. The fertilization event produces a zygote. The zygote then develops into an ookinete. The zygote and ookinete are the only diploid stages of "P. falciparum".

"Ookinete"

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

During the ookinete stage, genetic recombination can occur. This takes place if the ookinete was formed from male and female gametes derived from different populations. This can occur if the human host contained multiple populations of the parasite, or if the mosquito fed of multiple infected individuals within a short time-frame.

"Sporogony"

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

Cell Biology

Cell Division

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

Apical complex

Transport/Secretion

Ions

Parasitophorous Vacuole

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

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

Apicoplast

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

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

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

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

Genome

The genome of "Plasmodium falciparum" (clone 3D7) was fully sequenced in 2002. . The parasite has a 23 megabase genome, divided into 14 chromosomes. The genome codes for approximately 5,300 genes. About 60% of the putative proteins have little or no similarity to proteins in other organisms, and thus currently have no functional assignment.cite journal
last = Gardner
first = Malcom
authorlink =
coauthors =
title = Genome sequence of the human malaria parasite "Plasmodium falciparum"
journal = Nature
volume = 419
issue =
pages = 498–511
publisher =
location =
date = 3 October 2002
url = http://www.nature.com/nature/journal/v419/n6906/full/nature01097.html
doi =
id =
accessdate =
] It is estimated 52.6% of the genome is a coding region, with 53.9% of the putative genes containing at least one intron.

Haploid/Diploid

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

AT Richness

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

Promoters

ubtelomeric regions

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

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

Transcriptome

A transcriptome analysis has been conducted on the intraerythrocytic development cycle of "P. falciparum".cite journal
last = Bozdech
first = Zbynek
authorlink =
coauthors =
title = The Transcriptome of the Intraerythrocytic Developmental Cycle of Plasmodium falciparum
journal = PLoS Biology
volume = 1
issue = 1
pages =
publisher =
location =
date = August 18, 2003
url = http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pbio.0000005
doi =
id =
accessdate =
] Roughly 60% of the genome is transcriptionally active during this portion of the parasite's life cycle. Whereas many genes appear to have stable mRNA levels throughout the cycle, many of the genes are transcriptionally regulated in a continuous cascade.

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

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

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

Proteome

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

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

It is estimated that 4.7% of the proteome is targeted to the mictochondria.

The parasite has different subsets of its proteome expressed during various stages of its developmental cycle.cite journal
last = Florens
first =
authorlink =
coauthors =
title = A proteomic view of the "Plasmodium falciparum" life cycle
journal = Nature
volume = 419
issue =
pages = 520–526
publisher =
location =
date = 3 October 2002
doi =
id =
accessdate =
] In one study, of the 2,415 proteins were identified in four stages(sporozoite, merozoite, trophozoite, gametocyte), representing 46% of the theoretical number of proteins. Only 6% of the proteins were found in all of the four stages. Of the proteins found, 51% were annotated as hypothetical proteins.

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

Metabolism

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

Hemoglobin metabolism

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

Heme biosynthesis by the parasite has been reported.cite journal
last = Bonday
first = Z.Q.
authorlink =
coauthors =
title = Import of host delta-aminolevulinate dehydratase into the malarial parasite: Identification of a new drug target
journal = Nature Medicine
volume = 6
issue =
pages = 898–903
publisher =
location =
date = 2002
url = http://www.nature.com/nm/journal/v6/n8/full/nm0800_898.html#B1
doi =
id =
accessdate =
]

Carbohydrate metabolism

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

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

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

Protein metabolism

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

Lipid metabolism

Nucleotide metabolism

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

Conversely, the parasite can produce pyrimidines "de novo" using glutamine, bicarbonate, and aspartate.

Human immune system evasion

"var" family

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

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

"rif" family

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

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

"stevor" family

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

The function of the stevor proteins is currently unknown.

Research

Resources

[http://www.malaria.mr4.org/ MR4] , The NIAID funded Malaria Research and Reference ReagentResource Center

[http://www.plasmodb.org/plasmo/home.jsp PlasmoDB]

[http://malaria.ucsf.edu/comparison/ Malaria IDC Strain Comparison Database]

[http://malaria.ucsf.edu/ Malaria IDC Transcriptome Database]

[http://sites.huji.ac.il/malaria/ Malaria Parasite Metabolic Pathways]

[http://apicyc.apidb.org/ ApiCyc]

References


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