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Plasmodium berghei
Single celled parasite, rodent malaria From Wikipedia, the free encyclopedia
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Plasmodium berghei is a single-celled parasite causing rodent malaria. It is in the Plasmodium subgenus Vinckeia.
Originally, isolated from thicket rats in Central Africa,[3] P. berghei is one of four Plasmodium species that have been described in African murine rodents, the others are P. chabaudi, P. vinckei, and P. yoelii. Due to its ability to infect rodents and relative ease of genetic engineering, P. berghei is a popular model organism for the study of human malaria.[4]
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Biology
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Like all malarial parasites of mammals, including the four human malaria parasites, P. berghei is transmitted by Anopheles 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). The multiplication of the parasite in the blood causes the pathology such as anaemia 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.[5]
Although sexuality is necessary in vivo in P. berghei as normal for most sexual organisms, it is a stark competitive disadvantage in vitro. Sinha et al., 2014 implement both mechanical passaging and competitive assay to demonstrate the advantage of loss of gametocyte production: During mechanical passage successive generations are found to naturally trend toward lower gametocytaemia; and nonsexuals outcompete sexuals rapidly when placed together in vitro.[6]: 575
Immunochemistry
Endothelin 1 has an uncertain role in producing cerebral murine malaria.[2] Martins et al., 2016 find blockade of endothelin-1 prevents CMM and its symptoms and supplementation helps to produce it.[2] Subramaniam et al., 2015 find mice increase production of BTNL2 during infection and so it is probably protective.[2] Chertow et al., 2015 find the asymmetric dimethylarginine-to-arginine ratio is indicative of disease severity in mice with P. berghei ANKA.[7][8] This ratio is a metric of arginine bioavailability and in this disease they find it predicts degree of endothelial dysfunction.[7][8]
Pathophysiology
Liver stage
Before progressing to the symptomatic blood stage, P. Berghei infects the hepatocytes (liver cells), in which it undergoes rapid replication and generates thousands of merozoites that eventually burst and enter the bloodstream. The steps for this pathophysiological steps are as follows:
1) Hepatocyte Invasion - After being transmitted by an infected mosquito, Plasmodium sporozoites travel to the liver and invade hepatocytes.[9]
2)PV formation - Upon invasion, they create a parasitophorous vacuole (PV), which acts as a protective barrier against the cells's defense mechanisms in the cytoplasm. The PV is formed when the host cell invaginates (folds inward) around the invading parasite to enclose it within a protective compartment. This compartment provides shielding properties while also remaining permeable enough to allow for nutrient exchange so that the parasite continues to grow.[9][10]
3) Host manipulation - Inside the parasitophorous vacuole, The P. Berghei parasite alters host processes like the AQP3, UPR and autophagy pathways. This turns the cell defense mechanisms into tools that allow it to grow and expand.[10]
4) Parasite replication - Once the parasite establishes itself within the Hepatocyte by completing the previous steps of invasion, it undergoes rapid nuclear division through schizogony (a type of asexual reproduction utilized by malaria parasites). This causes each single host cell to hold tens of thousands of P. Berghei merozoites.[11]
5) Egress - Once the merozoites within the hepatocyte are fully mature and ready to invade red blood cells, the hepatocyte ruptures and the merozoites are release into the bloodstream. They begin invading circulating red blood cells and thus transition into the blood stage of malaria.[12]
Parasite evasion of the host immune system
Mosquito
P. berghei ookinetes express surface proteins P25 and P28 that protect against complement-like attack in the mosquito midgut by creating a protective coat.[13] Mosquito immune factor TEP1 binds to and destroys pathogens, but the membrane created by the surface proteins shield the ookinetes from the TEP1 mediated lysis. The parasite is also able to suppress encapsulation and melanization, which normally trap and kill invaders. Circumsporozoite proteins (CSP) and thrombosopondin-related anonymous protein (TRAP) mediate sporozoite entry into salivary glands without triggering immune detection.[14] CSP binds heparan sulfate proteoglycans to mosquito salivary gland cells. This allows sporozoites dock specifically where they need to invade, instead of constant circulation throughout the host organism. It also creates a dense coat around the sporozoite shielding other antigens from antibody recognitions.[15]
Liver
The sporozoites are able to traverse liver resident macrophages known as kupffer cells while suppressing reactive oxygen species and inflammatory cytokines allowing the immune response to be minimized and entry into the liver.[16] The parasitophorous vacuole proteins such as UIS3 and UIS4 blocks lysosomal fusion and hijacks host autophagy via LC3 binding.[17][18] The parasite once inside a hepatocyte is able to activate unfolded protein responses in the cell. In normal circumstances this induces the ER to perform apoptosis but in the case of the plasmodium parasite it is able to skew the pathway forcing it to begin expansion allowing the parasite to have more resources to feed on.[19] In addition to this the parasite also recruits host aquaporin-3 to import glycerol and water, further supporting growth.[20] Once the parasite is ready to leave the liver they are able egress as merosomes, meaning they are able to hide merozoites from the host macrophages by enveloping itself in a host derived vesicle[21].
Blood
After being released into the blood the parasite has antigenic variation, meaning it is able to switch surface antigens to avoid antibody detection, meaning it can avoid nearby leukocytes[22]. Once the plasmodium is able to infect a red blood cell it is able to undergo cytoadherence. Knobs on infected RBCs anchor to the endothelium, preventing it from circulating throughout the body. This allows the parasites to avoid splenic clearance.[23] They are also able to undergo rosetting, meaning that infected RBCs cluster with uninfected RBCs, physically shielding parasites from immune attack.[24]
Strains
Some strains produce cerebral murine malaria and some do not.[2]
- ANKA produces CMM.[2] Martins et al., 2016 find endothelin-1 production is vital to CMM disease progression.[1] Subramaniam et al., 2015 find mice respond to ANKA by increasing BTNL2.[2] Chertow et al., 2015 find arginine metabolism indicative of disease severity.[7][8]
- NK65 notably does not produce CMM.[2] Martins et al., 2016 find NK65 can produce CMM under supplementation of endothelin-1.[2]
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Hosts
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Plasmodium berghei was first identified in the thicket rat (Grammomys surdaster). It has also been described in Leggada bella, Praomys jacksoni and Thamnomys surdaster.[citation needed] In research laboratories, various rodents can be infected, such as mice (Mus musculus), rats and gerbils (Meriones unguiculatus).[25] In M. musculus ⇔ P. b. ANKA, downregulation of responses is necessary to prevent self-inflicted damage leading to CMM.[26][27]: 97 Specifically, Sarfo et al., 2011 finds mice produce the cytokine interleukin-10 (cIL-10) to suppress otherwise-potentially-deadly CMM damage from others of their own immune factors.[26][27]
The natural insect host of P. berghei is likely Anopheles dureni, however in laboratory conditions it has also been shown to infect An. stephensi.[citation needed]
Gene interactions
In Mus musculus ⇔ the P. b. ANKA strain various genes affect the incidence of cerebral murine malaria. Kassa et al., 2016 finds several genes to be of no effect:
- Apolipoprotein A-I (APOA1)[1]
- Low density lipoprotein receptor (LDLR)[1]
- Low density lipoprotein receptor-related protein 1 (LRP1)[1]
- Very low density lipoprotein receptor (VLDLR)[1]
They find one improves survival probability:
An. gambiae's hemocytes transcribe a wide array of molecular responses to Plasmodium infections.[28][29]: 138 [30][31][32][33]: 221 In response to this species, Baton et al., 2009 find this includes increased expression of the prophenoloxidase gene, cascading to increase phenoloxidase and thereby melanization.[28][29]: 138 [30][31][32][33]: 221
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Treatment
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Some phytochemicals show efficacy against P. berghei. Bankole et al., 2016 find Markhamia tomentosa to be highly effective, comparable to chloroquine, while Monoon longifolium is also significantly effective. They find Trichilia heudelotii to be ineffective.[34]
TMEM33 is an endoplasmic reticulum localized protein that is essential for all life cycle stages of Plasmodium berghei.[4] It is an important regulator of intracellular calcium homeostasis.[35] In humans and other eukaryotes, TMEM33 is a stress-inducible ER transmembrane protein, and is the regulator of UPR response elements.[36] UPR regulators and ER stress response elements play an important role in the blood stage infection and mosquito transmission of Plasmodium berghei.[4] Targeted deletions of TMEM33 show reduced parasitemia and mortality, indicating its potential as a drug target.[4]
The autophagy-related genes of Plasmodium berghei, PbATG5, PbATG8, and PbATG12 respond to 5-fluorouracil and chloroquine treatment, resulting in their upregulation and leading to apoptosis.[37]
History
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Plasmodium berghei is found in the forests of Central Africa, where its natural cyclic hosts are the thicket rat (Grammomys surdaster) and its vectors are the mosquitos: Anopheles dureni[38], Praomys jacksoni, and Leggada bella [39]. This species was first discovered by Ignace Vincke and Marcel Lips in blood films of Grammomys surdaster collected in Kisanga in the year 1948 in the Belgian Congo[40]. Plasmodium berghei was characterized by Dr. Richard Carter and David Walliker at the University of Edinburgh in the United Kingdom[41]. The parasite was then named after the director of the Institute for Scientific Research in Central Africa, Dr. Louis van den Berghe. A study conducted in 1950 by Vincke and Lips was the foundation for progressing the understanding of infectious process of P. berghei when infection became evident after injecting the isolated sporozoites into healthy mice [41]. P. berghei was the first in a series of three other malarial plasmodium (there are four total) to be discovered.[38]A trilogy of papers came out describing the discovery of this parasite and early analysis of the biology of P. berghei give an early indication of the natural host range of this parasite, a property that holds potential to underlying successful transmission of the parasite to a variety of laboratory hosts.[42] Though research only suggests that P. berghei is only a threat to rodents, it nevertheless gives us important insight on how to develops different types of medicine or antibiotics for the treatment of malaria.
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Research
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Plasmodium berghei infection of laboratory mouse strains is frequently used in research as a model for human malaria.[43] 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.
P. berghei is used as a model organism for the investigation of human malaria 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 in the blood vessels of the brain, it is unclear to what extent this occurs in mice infected with P. berghei.[43] Instead, in P. berghei infection, mice are found to have an accumulation of immune cells in brain blood vessels.[43] This has led some to question the use of P. berghei infections in mice as an appropriate model of cerebral malaria in humans.[43]
P. berghei can be genetically manipulated in the laboratory using standard genetic engineering technologies. Consequently, this parasite is often used for the analysis of the function of malaria genes using the technology of genetic modification.[44][45][46] Additionally, the genome of P. berghei has been sequenced and it shows a high similarity, both in structure and gene content, with the genome of the primate malaria parasite Plasmodium falciparum.[47][48][49]
A number of genetically modified P. berghei lines have been generated which express fluorescent reporter proteins such as Green Fluorescent Protein (GFP) and mCherry (red) or bioluminescent reporters such as Luciferase. These transgenic parasites are important tools to study and visualize the parasites in the living host.[50][51]
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.[52]
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Significance to One Health
Malaria is regarded as one of the most pervasive diseases in the world with the number of cases surpassing the hundreds of millions every year.[53] P. berghei zoonotic disease has a major impact on rodents within many different ecosystems and food chains around the world. While this parasite is not a threat to humans, it is used as a research tool for studying the life cycles, cellular biology, and pathogenicity of malaria within its animal hosts, which is then used for understanding its effects on human hosts. Understanding the intricacies of this parasite and how it operates allows for the development and improvement of vaccines and therapies that can then be distributed to areas where the risk for malaria within the human population is high. One strategy for combating this disease is by developing transmission blocking strategies (TBS) to stop the development of P. berghei within the mosquito stage, so that transmission may be halted all together.[53]
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References
External links
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