''Plasmodium berghei'' is a species in the genus ''

Plasmodium ''Plasmodium'' is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of ''Plasmodium'' species involve development in a blood-feeding insect host which then injects parasites into a vert ...

'' subgenus ''

Vinckeia ''Vinckeia'' is a subgenus of the genus ''Plasmodium'' — all of which are parasitic alveolates. The subgenus ''Vinckeia'' was created by Cyril Garnham in 1964 to accommodate the mammalian parasites other than those infecting the primates. Di ...

''. It is a

protozoan Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...

parasite Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has ...

that causes

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

in certain

rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...

s. Originally, isolated from thicket rats in Central Africa, ''P. berghei'' is one of four ''

'' species that have been described in African

murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...

rodents, the others being '' P. chabaudi'', '' P. vinckei'', and '' P. yoelii''. Due to its ability to infect rodents and relative ease of

genetic engineering Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...

, ''P. berghei'' is a popular

model organism A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

for the study of human malaria.

Biology

Like all malaria parasites of

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

s, including the four human

parasites, ''P. berghei'' is transmitted by ''

Anopheles ''Anopheles'' () is a genus of mosquito first described and named by J. W. Meigen in 1818. About 460 species are recognised; while over 100 can transmit human malaria, only 30–40 commonly transmit parasites of the genus ''Plasmodium'', which c ...

'' mosquitoes and it infects the liver after being injected into the bloodstream by a bite of an infected female mosquito. After a short period (a few days) of development and multiplication, these parasites leave the liver and invade

erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

(red blood cells). The multiplication of the parasite in the blood causes the pathology such as

anaemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

and damage of essential organs of the host such as lungs, liver, spleen. ''P. berghei'' infections may also affect the brain and can be the cause of cerebral complications in laboratory mice ( cerebral murine malaria, CMM). These symptoms are to a certain degree comparable to symptoms of cerebral malaria in patients infected with the human malaria parasite ''

Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...

''. Although

sexuality Human sexuality is the way people experience and express themselves sexually. This involves biological, psychological, physical, erotic, emotional, social, or spiritual feelings and behaviors. Because it is a broad term, which has varied ...

is necessary ''in vivo'' in ''P. berghei'' as normal for most sexual organisms, it is a stark

competitive disadvantage In business, a competitive advantage is an attribute that allows an organization to outperform its Competition (economics), competitors. A competitive advantage may include access to natural resources, such as high-grade ores or a low-cost powe ...

in vitro. Sinha ''et al.'', 2014 implement both

mechanical passaging Mechanical may refer to: Machine * Machine (mechanical), a system of mechanisms that shape the actuator input to achieve a specific application of output forces and movement * Mechanical calculator, a device used to perform the basic operations of ...

and competitive assay to demonstrate the advantage of loss of

gametocyte A 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''. Development ...

production: During mechanical passage successive generations are found to naturally trend toward lower gametocytaemia; and nonsexuals outcompete sexuals rapidly when placed together ''in vitro''.

Immunochemistry

Endothelin 1 Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells. The protein encoded by this gene ''EDN1'' is proteolytically processed to release endothelin 1. Endotheli ...

has an uncertain role in producing cerebral murine malaria. Martins ''et al.'', 2016 find blockade of endothelin-1 ''prevents'' CMM and its symptoms and supplementation helps to ''produce'' it. Subramaniam ''et al.'', 2015 find mice increase production of

BTNL2 Butyrophilin-like protein 2 is a protein that in humans is encoded by the ''BTNL2'' gene. Because it is associated with the immune system and the major histocompatibility complex, it has been implicated in many diseases (see further reading list ...

during infection and so it is probably protective. Chertow ''et al.'', 2015 find the asymmetric dimethylarginine-to-

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

''ratio'' is indicative of disease severity in mice with ''P. berghei'' ANKA. This ratio is a metric of arginine

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

and in this disease they find it predicts degree of endothelial dysfunction.

Strains

Some strains produce cerebral murine malaria and some do not. * produces CMM. Martins ''et al.'', 2016 find endothelin-1 production is vital to CMM disease progression. Subramaniam ''et al.'', 2015 find mice respond to ANKA by increasing BTNL2. Chertow ''et al.'', 2015 find arginine metabolism indicative of disease severity. * notably does not produce CMM. Martins ''et al.'', 2016 find NK65 ''can'' produce CMM under supplementation of endothelin-1. See section above for specific molecules' interactions.

Distribution

''Plasmodium berghei'' is found in the forests of

Central Africa Central Africa is a subregion of the African continent comprising various countries according to different definitions. Angola, Burundi, the Central African Republic, Chad, the Democratic Republic of the Congo, the Republic of the Congo, ...

, where its natural cyclic hosts are the thicket rat (''

Grammomys ''Grammomys'' is a genus of rodent in the family Muridae endemic to Africa. It contains the following species: * Arid thicket rat (''Grammomys aridulus'') * Short-snouted thicket rat (''Grammomys brevirostris'') * Bunting's thicket rat (''Gramm ...

surdaster'') and the

mosquito Mosquitoes (or mosquitos) are members of a group of almost 3,600 species of small flies within the family Culicidae (from the Latin ''culex'' meaning " gnat"). The word "mosquito" (formed by ''mosca'' and diminutive ''-ito'') is Spanish for "li ...

('' Anopheles dureni'').

Hosts

''Plasmodium berghei'' was first identified in the thicket rat (''

surdaster''). It has also been described in '' Leggada bella'', ''

Praomys jacksoni Jackson's soft-furred mouse or Jackson's praomys (''Praomys jacksoni'') is a species of rodent in the family Muridae. It is found in Angola, Burundi, Cameroon, Central African Republic, Republic of the Congo, Democratic Republic of the Congo, ...

'' and ''

Thamnomys ''Thamnomys'' is a genus of Old World rats from East Central Africa Africa is the world's second-largest and second-most populous continent, after Asia in both cases. At about 30.3 million km2 (11.7 million square miles) ...

surdaster.'' In research laboratories, various rodents can be infected, such as mice (''

Mus musculus Mus or MUS may refer to: Abbreviations * MUS, the NATO country code for Mauritius * MUS, the IATA airport code for Minami Torishima Airport * MUS, abbreviation for the Centre for Modern Urban Studies on Campus The Hague, Leiden University, Neth ...

''), rats and gerbils ('' Meriones unguiculatus''). In ''M. musculus'' ⇔ ''P. b.'' ANKA, downregulation of responses is necessary to prevent self-inflicted damage leading to CMM. Specifically, Sarfo ''et al.'', 2011 finds mice produce the cytokine

interleukin-10 Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti- inflammatory cytokine. In humans, interleukin 10 is encoded by the ''IL10'' gene. IL-10 signals through a receptor complex consisting of two IL-10 ...

(cIL-10) to suppress otherwise-potentially-deadly CMM damage from others of their own immune factors. The natural insect host of ''P. berghei'' is likely '' Anopheles dureni'', however in laboratory conditions it has also been shown to infect '' An. stephensi''.

Gene interactions

In ''

'' ⇔ the ''P. b.'' ANKA strain various

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s affect the incidence of cerebral murine malaria. Kassa ''et al.'', 2016 finds several

s to be of no effect: * Apolipoprotein A-I (''

APOA1 Apolipoprotein AI (ApoA-I) is a protein that in humans is encoded by the ''APOA1'' gene. As the major component of HDL particles, it has a specific role in lipid metabolism. Structure ''APOA1'' is located on chromosome 11, with its specific lo ...

'') * Low density lipoprotein receptor ('' LDLR'') * Low density lipoprotein receptor-related protein 1 (''

LRP1 Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membr ...

'') * Very low density lipoprotein receptor (''

VLDLR The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, ...

'') They find one improves survival probability: *

Apolipoprotein E Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...

(''

APOE Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...

'') '' An. gambiae''s

hemocyte A blood cell, also called a hematopoietic cell, hemocyte, or hematocyte, is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), a ...

s transcribe a wide array of molecular responses to ''Plasmodium'' infections. NIHMSID 615755. In response to this species, Baton ''et al.'', 2009 find this includes increased expression of the ''

prophenoloxidase Prophenoloxidase (proPO) is a modified form of the complement response found in some invertebrates, including insects, crabs and worms. It is a copper-containing metalloprotein. A major innate defense system in invertebrates is the melanizatio ...

'' gene, cascading to increase

phenoloxidase Polyphenol oxidase (PPO; also polyphenol oxidase i, chloroplastic), an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule. PPO may accept monophenols and/or ''o''-diphenols as substrates. The ...

and thereby

melanization Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amin ...

Treatment

Some

phytochemical Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poisons ...

s show efficacy against ''P. berghei''. Bankole ''et al.'', 2016 find ''

Markhamia ''Markhamia'' is a genus of flowering plants in the family Bignoniaceae. The genus is named after Clements Markham. Species * ''Markhamia lutea'' (Benth.) K.Schum. * '' Markhamia obtusifolia'' (Baker) Sprague * ''Markhamia stipulata ''Mark ...

tomentosa'' to be highly effective, comparable to

chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...

, while ''

Monoon longifolium ''Monoon longifolium'', the false ashoka, also commonly known by its synonym ''Polyalthia longifolia'', is an Asian small tree species in the family Annonaceae. It is native to southern India and Sri Lanka, but has been widely introduced els ...

'' is also significantly effective. They find ''

Trichilia ''Trichilia'' is a flowering plant genus in the family Meliaceae. These plants are particularly diverse in sub-Saharan Africa and tropical South America. Several species are used in folk medicine and shamanism – e.g. '' T. rubescens'' ag ...

heudelotii'' to be ineffective.

History

This species was first described by Vincke and Lips in 1948 in the

Belgian Congo The Belgian Congo (french: Congo belge, ; nl, Belgisch-Congo) was a Belgian colony in Central Africa from 1908 until independence in 1960. The former colony adopted its present name, the Democratic Republic of the Congo (DRC), in 1964. Colo ...

.Vincke, I.H. and Lips, M. (1948) Un nouveau plasmodium d'un rongeur sauvage du Congo: ''Plasmodium berghei'' n.sp. Annales de la Société Belge de Médecine Tropicale 28, 97-104 Liver stage malaria parasite

Research

''Plasmodium berghei'' infection of laboratory mouse strains is frequently used in research as a model for human malaria. In the laboratory the natural hosts have been replaced by a number of commercially available laboratory mouse strains, and the mosquito ''Anopheles stephensi'', which is comparatively easily reared and maintained under defined laboratory conditions. ''Plasmodium berghei'' is used as a model organism for the investigation of human

because of its similarity to the ''Plasmodium'' species which cause human malaria. ''P. berghei'' has a very similar life-cycle to the species that infect humans, and it causes disease in mice which has signs similar to those seen in human malaria. Importantly, ''P. berghei'' can be genetically manipulated more easily than the species which infect humans, making it a useful model for research into ''Plasmodium'' genetics. In several aspects the pathology caused by ''P. berghei'' in mice differs from malaria caused by ''P. falciparum'' in humans. In particular, while death from ''P. falciparum'' malaria in humans is most frequently caused by the accumulation of

red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...

in the blood vessels of the brain, it is unclear to what extent this occurs in mice infected with ''P. berghei''. Instead, in ''P. berghei'' infection, mice are found to have an accumulation of

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

in brain blood vessels. This has led some to question the use of ''P. berghei'' infections in mice as an appropriate model of cerebral malaria in humans. ''Plasmodium berghei'' can be genetically manipulated in the laboratory using standard

technologies. Consequently, this parasite is often used for the analysis of the function of malaria genes using the technology of

genetic modification Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...

. Additionally, the

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...

of ''P. berghei'' has been sequenced and it shows a high similarity, both in structure and

content, with the genome of the primate malaria parasite ''

''. A number of genetically modified ''P. berghei'' lines have been generated which express fluorescent reporter proteins such as

Green Fluorescent Protein The green fluorescent protein (GFP) is a protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. The label ''GFP'' traditionally refers to the protein first isolated from the jellyfish ''Aequorea ...

(GFP) and

mCherry mCherry is a member of the mFruits family of monomeric red fluorescent proteins (mRFPs). As a RFP, mCherry was derived from DsRed of '' Discosoma'' sea anemones unlike green fluorescent proteins (GFPs) which are often derived from '' Aequoera vic ...

(red) or

bioluminescent Bioluminescence is the production and emission of light by living organisms. It is a form of chemiluminescence. Bioluminescence occurs widely in marine vertebrates and invertebrates, as well as in some Fungus, fungi, microorganisms including ...

reporters such as

Luciferase Luciferase is a generic term for the class of oxidative enzymes that produce bioluminescence, and is usually distinguished from a photoprotein. The name was first used by Raphaël Dubois who invented the words ''luciferin'' and ''luciferase'', ...

. These transgenic parasites are important tools to study and visualize the parasites in the living host. ''P. berghei'' is used in research programs for development and screening of anti-malarial drugs and for the development of an effective vaccine against malaria.

References

External links

{{Scholia, topic ;General information about (the biology of) ''P. berghei'':
www.pberghei.nl/homepage/model-of-malaria
;Information about the genome and genes of ''P. berghei'':
www.pberghei.euplasmogem.sanger.ac.ukwww.plasmodb.org/plasmo/appwww.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&Cmd=Search&Term=txid5821
berghei Parasites of rodents