Plasmodium berghei

Like all malaria 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.{{cite journal | vauthors = Franke-Fayard B, Fonager J, Braks A, Khan SM, Janse CJ | title = Sequestration and tissue accumulation of human malaria parasites: can we learn anything from rodent models of malaria? | journal = PLOS Pathogens | volume = 6 | issue = 9 | pages = e1001032 | date = September 2010 | pmid = 20941396 | pmc = 2947991 | doi = 10.1371/journal.ppat.1001032 | doi-access = free }}

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.{{cite journal | vauthors = Josling GA, Llinás M | title = Sexual development in Plasmodium parasites: knowing when it's time to commit | journal = Nature Reviews. Microbiology | volume = 13 | issue = 9 | pages = 573–587 | date = September 2015 | pmid = 26272409 | doi = 10.1038/nrmicro3519 | publisher = Nature Portfolio | s2cid = 2182486 }}{{rp|575}}

Endothelin 1 has an uncertain role in producing cerebral murine malaria.{{cite journal | vauthors = Moxon CA, Gibbins MP, McGuinness D, Milner DA, Marti M | title = New Insights into Malaria Pathogenesis | journal = Annual Review of Pathology | volume = 15 | issue = 1 | pages = 315–343 | date = January 2020 | pmid = 31648610 | doi = 10.1146/annurev-pathmechdis-012419-032640 | publisher = Annual Reviews | s2cid = 204882296 }} 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 during infection and so it is probably protective. Chertow et al., 2015 find the asymmetric dimethylarginine-to-arginine ratio is indicative of disease severity in mice with P. berghei ANKA.{{cite journal | vauthors = Ngai M, Weckman AM, Erice C, McDonald CR, Cahill LS, Sled JG, Kain KC | title = Malaria in Pregnancy and Adverse Birth Outcomes: New Mechanisms and Therapeutic Opportunities | journal = Trends in Parasitology | volume = 36 | issue = 2 | pages = 127–137 | date = February 2020 | pmid = 31864896 | doi = 10.1016/j.pt.2019.12.005 | publisher = Cell Press | s2cid = 209446589 }}{{cite journal | vauthors = Kayano AC, Dos-Santos JC, Bastos MF, Carvalho LJ, Aliberti J, Costa FT | title = Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria | journal = Infection and Immunity | volume = 84 | issue = 4 | pages = 874–882 | date = April 2016 | pmid = 26831465 | pmc = 4807480 | doi = 10.1128/iai.01404-15 | publisher = American Society for Microbiology | s2cid = 29927044 | veditors = Andrews-Polymenis HL }} This ratio is a metric of arginine bioavailability and in this disease they find it predicts degree of endothelial dysfunction.

Some strains produce cerebral murine malaria and some do not.

• {{ visible anchor |ANKA}} 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.
• {{ visible anchor |NK65}} 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.

Plasmodium berghei is found in the forests of Central Africa, where its natural cyclic hosts are the thicket rat (Grammomys surdaster) and the mosquito (Anopheles dureni).

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|date=January 2016}} In research laboratories, various rodents can be infected, such as mice (Mus musculus), rats and gerbils (Meriones unguiculatus).{{cite journal | vauthors = Junaid QO, Khaw LT, Mahmud R, Ong KC, Lau YL, Borade PU, Liew JW, Sivanandam S, Wong KT, Vythilingam I| title = Pathogenesis of Plasmodium berghei ANKA infection in the gerbil (Meriones unguiculatus) as an experimental model for severe malaria | journal = Parasite | volume = 24 | pages = 38 | year = 2017 | pmid = 29034874 | pmc = 5642054 | doi = 10.1051/parasite/2017040 }} {{open access}} In M. musculus ⇔ P. b. ANKA, downregulation of responses is necessary to prevent self-inflicted damage leading to CMM.{{cite journal | vauthors = Xu Z, Zhang X, Lau J, Yu J | title = C-X-C motif chemokine 10 in non-alcoholic steatohepatitis: role as a pro-inflammatory factor and clinical implication | journal = Expert Reviews in Molecular Medicine | volume = 18 | pages = e16 | date = September 2016 | pmid = 27669973 | doi = 10.1017/erm.2016.16 | publisher = Cambridge University Press (CUP) | s2cid = 28322523 }}{{cite book | vauthors = Fillatreau S, O'Garra A |series=Current Topics in Microbiology and Immunology| title=Interleukin-10 in Health and Disease | journal=International Journal of Molecular Sciences | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | year=2014 | volume=20 | issue=3 | page=649 | doi=10.1007/978-3-662-43492-5 | pmid=30717382 | pmc=6387150 | isbn=978-3-662-43491-8 | issn=0070-217X}}{{rp|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.

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|date=January 2016}}

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){{cite journal | vauthors = Torre S, Langlais D, Gros P | title = Genetic analysis of cerebral malaria in the mouse model infected with Plasmodium berghei | journal = Mammalian Genome | volume = 29 | issue = 7–8 | pages = 488–506 | date = August 2018 | pmid = 29922917 | doi = 10.1007/s00335-018-9752-9 | publisher = Springer Science+Business Media | s2cid = 49309005 | id = International Mammalian Genome Society }}
• Low density lipoprotein receptor (LDLR)
• Low density lipoprotein receptor-related protein 1 (LRP1)
• Very low density lipoprotein receptor (VLDLR)

They find one improves survival probability:

• Apolipoprotein E (APOE)

An. gambiae{{'}}s hemocytes transcribe a wide array of molecular responses to Plasmodium infections.{{cite journal | vauthors = Smith RC, Vega-Rodríguez J, Jacobs-Lorena M | title = The Plasmodium bottleneck: malaria parasite losses in the mosquito vector | journal = Memórias do Instituto Oswaldo Cruz | volume = 109 | issue = 5 | pages = 644–661 | date = August 2014 | pmid = 25185005 | pmc = 4156458 | doi = 10.1590/0074-0276130597 | publisher = FapUNIFESP (SciELO) }}{{cite book | veditors = Gilbert LI | vauthors = Willis JH, Papandreou NC, Iconomidou VA, Hamodrakas SJ | title=Insect Molecular Biology and Biochemistry | chapter=5 Cuticular Proteins | publisher=Elsevier | year=2012 | isbn=978-0-12-384747-8 | oclc=742299021 | pages=x+563}}{{rp|138}}{{cite journal | vauthors = Clayton AM, Dong Y, Dimopoulos G | title = The Anopheles innate immune system in the defense against malaria infection | journal = Journal of Innate Immunity | volume = 6 | issue = 2 | pages = 169–181 | year = 2014 | pmid = 23988482 | pmc = 3939431 | doi = 10.1159/000353602 | publisher = Karger Publishers }}{{cite journal | vauthors = Hillyer JF, Strand MR | title = Mosquito hemocyte-mediated immune responses | journal = Current Opinion in Insect Science | volume = 3 | pages = 14–21 | date = September 2014 | pmid = 25309850 | pmc = 4190037 | doi = 10.1016/j.cois.2014.07.002 | publisher = Elsevier | id = NIHMSID 615755 | bibcode = 2014COIS....3...14H }}{{cite journal | vauthors = Cheng G, Liu Y, Wang P, Xiao X | title = Mosquito Defense Strategies against Viral Infection | journal = Trends in Parasitology | volume = 32 | issue = 3 | pages = 177–186 | date = March 2016 | pmid = 26626596 | pmc = 4767563 | doi = 10.1016/j.pt.2015.09.009 | publisher = Cell Press }}{{cite book | veditors = Söderhäll K | vauthors = Hillyer JF | title=Invertebrate Immunity | chapter=Mosquito Immunity |series=Advances in Experimental Medicine and Biology| publisher=Springer Nature | publication-place=Boston, MA | year=2010 | volume=708 | isbn=978-1-4419-8058-8 | issn=0065-2598 | doi=10.1007/978-1-4419-8059-5_12 | pages=218–238| pmid=21528701 }}{{rp|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.{{rp|138}}{{rp|221}}

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.{{cite journal | vauthors = Dkhil MA, Al-Quraishy S, Al-Shaebi EM, Abdel-Gaber R, Thagfan FA, Qasem MA | title = Medicinal plants as a fight against murine blood-stage malaria | journal = Saudi Journal of Biological Sciences | volume = 28 | issue = 3 | pages = 1723–1738 | date = March 2021 | pmid = 33732056 | pmc = 7938113 | doi = 10.1016/j.sjbs.2020.12.014 | publisher = Elsevier | s2cid = 232241302 | id = Saudi Biological Society | bibcode = 2021SJBS...28.1723D }}

TMEM33 is an endoplasmic reticulum localized protein that is essential for all life cycle stages of Plasmodium berghei. It is an important regulator of intracellular calcium homeostasis.{{cite journal | vauthors = Arhatte M, Gunaratne GS, El Boustany C, Kuo IY, Moro C, Duprat F, Plaisant M, Duval H, Li D, Picard N, Couvreux A, Duranton C, Rubera I, Pagnotta S, Lacas-Gervais S, Ehrlich BE, Marchant JS, Savage AM, van Eeden FJ, Wilkinson RN, Demolombe S, Honoré E, Patel A| title = TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells | journal = Nature Communications | volume = 10 | issue = 1 | pages = 2024 | date = May 2019 | pmid = 31048699 | pmc = 6497644 | doi = 10.1038/s41467-019-10045-y | bibcode = 2019NatCo..10.2024A }} In humans and other eukaryotes, TMEM33 is a stress-inducible ER transmembrane protein, and is the regulator of UPR response elements.{{cite journal | vauthors = Sakabe I, Hu R, Jin L, Clarke R, Kasid UN | title = TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling | journal = Breast Cancer Research and Treatment | volume = 153 | issue = 2 | pages = 285–297 | date = September 2015 | pmid = 26268696 | pmc = 4559576 | doi = 10.1007/s10549-015-3536-7 }} UPR regulators and ER stress response elements play an important role in the blood stage infection and mosquito transmission of Plasmodium berghei. Targeted deletions of TMEM33 show reduced parasitemia and mortality, indicating its potential as a drug target.

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.{{cite journal | vauthors = Unal S, Kina UY, Kamil M, Aly AS, Palabiyik B | title = Drug-induced ER stress leads to induction of programmed cell death pathways of the malaria parasite | journal = Parasitology Research | volume = 123 | issue = 7 | pages = 263 | date = July 2024 | pmid = 38976068 | pmc = 11230985 | doi = 10.1007/s00436-024-08281-3 }}

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

Image:Berghei 02.png (green) in erythrocytes; visualised using a fluorescence microscope]]

Image:Berghei 03.png. Transgenic parasites are visualized by their expression of the bioluminescent reporter protein Luciferase]]

File:Liver stage malaria parasite.jpg (red). Here the parasite membrane is stained green with an antibody, while the nuclei of liver cells and parasites are stained with DAPI (blue)]]

Plasmodium berghei infection of laboratory mouse strains is frequently used in research as a model for human malaria.{{cite journal | vauthors = Craig AG, Grau GE, Janse C, Kazura JW, Milner D, Barnwell JW, Turner G, Langhorne J| title = The role of animal models for research on severe malaria | journal = PLOS Pathogens | volume = 8 | issue = 2 | pages = e1002401 | date = February 2012 | pmid = 22319438 | pmc = 3271056 | doi = 10.1371/journal.ppat.1002401 | doi-access = free }} 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. Instead, in P. berghei infection, mice are found to have an accumulation of immune cells 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.

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.{{cite journal | vauthors = Janse CJ, Ramesar J, Waters AP | title = High-efficiency transfection and drug selection of genetically transformed blood stages of the rodent malaria parasite Plasmodium berghei | journal = Nature Protocols | volume = 1 | issue = 1 | pages = 346–356 | date = 2006 | pmid = 17406255 | doi = 10.1038/nprot.2006.53 | s2cid = 20096737 }}{{cite journal | vauthors = Janse CJ, Kroeze H, van Wigcheren A, Mededovic S, Fonager J, Franke-Fayard B, Waters AP, Khan SM| title = A genotype and phenotype database of genetically modified malaria-parasites | journal = Trends in Parasitology | volume = 27 | issue = 1 | pages = 31–39 | date = January 2011 | pmid = 20663715 | doi = 10.1016/j.pt.2010.06.016 }}{{cite book|author1=Khan SM |author2=Kroeze H |author3=Franke-Fayard B |author4=Janse CJ |title=Malaria |chapter=Standardization in Generating and Reporting Genetically Modified Rodent Malaria Parasites: The RMGMDB Database |date=2013 |volume=923 |pages=139–50 |pmid=22990775 |doi=10.1007/978-1-62703-026-7_9|series=Methods in Molecular Biology|isbn=978-1-62703-025-0 }} 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.{{cite journal | vauthors = Hall N, Karras M, Raine JD, Carlton JM, Kooij TW, Berriman M, Florens L, Janssen CS, Pain A, Christophides GK, James K, Rutherford K, Harris B, Harris D, Churcher C, Quail MA, Ormond D, Doggett J, Trueman HE, Mendoza J, Bidwell SL, Rajandream MA, Carucci DJ, Yates JR, Kafatos FC, Janse CJ, Barrell B, Turner CM, Waters AP, Sinden RE| title = A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses | journal = Science | volume = 307 | issue = 5706 | pages = 82–86 | date = January 2005 | pmid = 15637271 | doi = 10.1126/science.1103717 | s2cid = 7230793 | bibcode = 2005Sci...307...82H }}{{cite journal | vauthors = Kooij TW, Janse CJ, Waters AP | title = Plasmodium post-genomics: better the bug you know? | journal = Nature Reviews. Microbiology | volume = 4 | issue = 5 | pages = 344–357 | date = May 2006 | pmid = 16582929 | doi = 10.1038/nrmicro1392 | s2cid = 38403613 | doi-access = free }}{{cite journal | vauthors = Otto TD, Böhme U, Jackson AP, Hunt M, Franke-Fayard B, Hoeijmakers WA, Religa AA, Robertson L, Sanders M, Ogun SA, Cunningham D, Erhart A, Billker O, Khan SM, Stunnenberg HG, Langhorne J, Holder AA, Waters AP, Newbold CI, Pain A, Berriman M, Janse CJ| title = A comprehensive evaluation of rodent malaria parasite genomes and gene expression | journal = BMC Biology | volume = 12 | pages = 86 | date = October 2014 | pmid = 25359557 | pmc = 4242472 | doi = 10.1186/s12915-014-0086-0 | doi-access = free }}

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.{{cite journal | vauthors = Amino R, Ménard R, Frischknecht F | title = In vivo imaging of malaria parasites--recent advances and future directions | journal = Current Opinion in Microbiology | volume = 8 | issue = 4 | pages = 407–414 | date = August 2005 | pmid = 16019254 | doi = 10.1016/j.mib.2005.06.019 }}{{cite journal | vauthors = Franke-Fayard B, Waters AP, Janse CJ | title = Real-time in vivo imaging of transgenic bioluminescent blood stages of rodent malaria parasites in mice | journal = Nature Protocols | volume = 1 | issue = 1 | pages = 476–485 | year = 2006 | pmid = 17406270 | doi = 10.1038/nprot.2006.69 | s2cid = 20812965 }}

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.{{cite journal | vauthors = Khan SM, Janse CJ, Kappe SH, Mikolajczak SA | title = Genetic engineering of attenuated malaria parasites for vaccination | journal = Current Opinion in Biotechnology | volume = 23 | issue = 6 | pages = 908–916 | date = December 2012 | pmid = 22560204 | doi = 10.1016/j.copbio.2012.04.003 }}

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;General information about (the biology of) P. berghei:

• [https://www.pberghei.nl/homepage/model-of-malaria www.pberghei.nl/homepage/model-of-malaria]

;Information about the genome and genes of P. berghei:

• [https://www.pberghei.eu www.pberghei.eu]
• [https://plasmogem.sanger.ac.uk plasmogem.sanger.ac.uk]
• [https://www.plasmodb.org/plasmo/app www.plasmodb.org/plasmo/app]
• [https://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&Cmd=Search&Term=txid5821 www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&Cmd=Search&Term=txid5821]

berghei

berghei

Category:Parasites of rodents