Biology:Plasmodium berghei

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Short description: Single celled parasite, rodent malaria

Plasmodium berghei
Blood-borne forms
Blood-borne forms
Scientific classification edit
Domain: Eukaryota
Clade: Diaphoretickes
Clade: SAR
Clade: Alveolata
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemospororida
Family: Plasmodiidae
Genus: Plasmodium
Species:
P. berghei
Binomial name
Plasmodium berghei
Vincke & Lips, 1948
Strains

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 being 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]

Biology

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.[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]

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]

See section above for specific molecules' interactions.

Distribution

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).

Hosts

Plasmodium berghei was first identified in the thicket rat (Grammomys surdaster). It has also been described in Leggada bella, Praomys jacksoni and Thamnomys surdaster. In research laboratories, various rodents can be infected, such as mice (Mus musculus), rats and gerbils (Meriones unguiculatus).[9] In M. musculus ⇔ P. b. ANKA, downregulation of responses is necessary to prevent self-inflicted damage leading to CMM.[10][11]: 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.[10][11]


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:

  • Apolipoprotein E (APOE)[1]

An. gambiae's hemocytes transcribe a wide array of molecular responses to Plasmodium infections.[12][13]: 138 [14][15][16][17]: 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.[12][13]: 138 [14][15][16][17]: 221 

Treatment

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.[18]

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.[19] In humans and other eukaryotes, TMEM33 is a stress-inducible ER transmembrane protein, and is the regulator of UPR response elements.[20] 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.[21]

History

This species was first described by Vincke and Lips in 1948 in the Belgian Congo.[22]

Live P. berghei expressing GFP (green) in erythrocytes; visualised using a fluorescence microscope
Infected mouse, with P. berghei in the lungs, spleen and adipose tissue. Transgenic parasites are visualized by their expression of the bioluminescent reporter protein Luciferase
A liver cell with P. berghei (a schizont with daughter parasites) expressing mCherry (red). Here the parasite membrane is stained green with an antibody, while the nuclei of liver cells and parasites are stained with DAPI (blue)

Research

Plasmodium berghei infection of laboratory mouse strains is frequently used in research as a model for human malaria.[23] 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.[23] Instead, in P. berghei infection, mice are found to have an accumulation of immune cells in brain blood vessels.[23] This has led some to question the use of P. berghei infections in mice as an appropriate model of cerebral malaria in humans.[23]

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.[24][25][26] 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.[27][28][29]

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.[30][31]

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.[32]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Genetic analysis of cerebral malaria in the mouse model infected with Plasmodium berghei". Mammalian Genome (Springer Science+Business Media) 29 (7–8): 488–506. August 2018. doi:10.1007/s00335-018-9752-9. International Mammalian Genome Society. PMID 29922917. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "New Insights into Malaria Pathogenesis". Annual Review of Pathology (Annual Reviews) 15 (1): 315–343. January 2020. doi:10.1146/annurev-pathmechdis-012419-032640. PMID 31648610. 
  3. ↑ "Grammomys surdaster, the Natural Host for Plasmodium berghei Parasites, as a Model to Study Whole-Organism Vaccines Against Malaria". The American Journal of Tropical Medicine and Hygiene 96 (4): 835–841. April 2017. doi:10.4269/ajtmh.16-0745. PMID 28115674. 
  4. ↑ 4.0 4.1 4.2 4.3 "Endoplasmic reticulum localized TMEM33 domain-containing protein is crucial for all life cycle stages of the malaria parasite". Molecular Microbiology 121 (4): 767–780. April 2024. doi:10.1111/mmi.15228. PMID 38238886. 
  5. ↑ "Sequestration and tissue accumulation of human malaria parasites: can we learn anything from rodent models of malaria?". PLOS Pathogens 6 (9). September 2010. doi:10.1371/journal.ppat.1001032. PMID 20941396. 
  6. ↑ "Sexual development in Plasmodium parasites: knowing when it's time to commit". Nature Reviews. Microbiology (Nature Portfolio) 13 (9): 573–587. September 2015. doi:10.1038/nrmicro3519. PMID 26272409. 
  7. ↑ 7.0 7.1 7.2 "Malaria in Pregnancy and Adverse Birth Outcomes: New Mechanisms and Therapeutic Opportunities". Trends in Parasitology (Cell Press) 36 (2): 127–137. February 2020. doi:10.1016/j.pt.2019.12.005. PMID 31864896. 
  8. ↑ 8.0 8.1 8.2 "Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria". Infection and Immunity (American Society for Microbiology) 84 (4): 874–882. April 2016. doi:10.1128/iai.01404-15. PMID 26831465. 
  9. ↑ "Pathogenesis of Plasmodium berghei ANKA infection in the gerbil (Meriones unguiculatus) as an experimental model for severe malaria". Parasite 24: 38. 2017. doi:10.1051/parasite/2017040. PMID 29034874.  open access
  10. ↑ 10.0 10.1 "C-X-C motif chemokine 10 in non-alcoholic steatohepatitis: role as a pro-inflammatory factor and clinical implication". Expert Reviews in Molecular Medicine (Cambridge University Press (CUP)) 18. September 2016. doi:10.1017/erm.2016.16. PMID 27669973. 
  11. ↑ 11.0 11.1 Interleukin-10 in Health and Disease. Current Topics in Microbiology and Immunology. 20. Berlin, Heidelberg: Springer Berlin Heidelberg. 2014. 649. doi:10.1007/978-3-662-43492-5. ISBN 978-3-662-43491-8. 
  12. ↑ 12.0 12.1 "The Plasmodium bottleneck: malaria parasite losses in the mosquito vector". Memórias do Instituto Oswaldo Cruz (FapUNIFESP (SciELO)) 109 (5): 644–661. August 2014. doi:10.1590/0074-0276130597. PMID 25185005. 
  13. ↑ 13.0 13.1 "5 Cuticular Proteins". Insect Molecular Biology and Biochemistry. Elsevier. 2012. pp. x+563. ISBN 978-0-12-384747-8. OCLC 742299021. 
  14. ↑ 14.0 14.1 "The Anopheles innate immune system in the defense against malaria infection". Journal of Innate Immunity (Karger Publishers) 6 (2): 169–181. 2014. doi:10.1159/000353602. PMID 23988482. 
  15. ↑ 15.0 15.1 "Mosquito hemocyte-mediated immune responses". Current Opinion in Insect Science (Elsevier) 3: 14–21. September 2014. doi:10.1016/j.cois.2014.07.002. NIHMSID 615755. PMID 25309850. Bibcode: 2014COIS....3...14H. 
  16. ↑ 16.0 16.1 "Mosquito Defense Strategies against Viral Infection". Trends in Parasitology (Cell Press) 32 (3): 177–186. March 2016. doi:10.1016/j.pt.2015.09.009. PMID 26626596. 
  17. ↑ 17.0 17.1 "Mosquito Immunity". Invertebrate Immunity. Advances in Experimental Medicine and Biology. 708. Boston, MA: Springer Nature. 2010. pp. 218–238. doi:10.1007/978-1-4419-8059-5_12. ISBN 978-1-4419-8058-8. 
  18. ↑ "Medicinal plants as a fight against murine blood-stage malaria". Saudi Journal of Biological Sciences (Elsevier) 28 (3): 1723–1738. March 2021. doi:10.1016/j.sjbs.2020.12.014. Saudi Biological Society. PMID 33732056. Bibcode: 2021SJBS...28.1723D. 
  19. ↑ "TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells". Nature Communications 10 (1): 2024. May 2019. doi:10.1038/s41467-019-10045-y. PMID 31048699. Bibcode: 2019NatCo..10.2024A. 
  20. ↑ "TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling". Breast Cancer Research and Treatment 153 (2): 285–297. September 2015. doi:10.1007/s10549-015-3536-7. PMID 26268696. 
  21. ↑ "Drug-induced ER stress leads to induction of programmed cell death pathways of the malaria parasite". Parasitology Research 123 (7): 263. July 2024. doi:10.1007/s00436-024-08281-3. PMID 38976068. 
  22. ↑ 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
  23. ↑ 23.0 23.1 23.2 23.3 "The role of animal models for research on severe malaria". PLOS Pathogens 8 (2). February 2012. doi:10.1371/journal.ppat.1002401. PMID 22319438. 
  24. ↑ "High-efficiency transfection and drug selection of genetically transformed blood stages of the rodent malaria parasite Plasmodium berghei". Nature Protocols 1 (1): 346–356. 2006. doi:10.1038/nprot.2006.53. PMID 17406255. 
  25. ↑ "A genotype and phenotype database of genetically modified malaria-parasites". Trends in Parasitology 27 (1): 31–39. January 2011. doi:10.1016/j.pt.2010.06.016. PMID 20663715. 
  26. ↑ Khan SM; Kroeze H; Franke-Fayard B; Janse CJ (2013). "Standardization in Generating and Reporting Genetically Modified Rodent Malaria Parasites: The RMGMDB Database". Malaria. Methods in Molecular Biology. 923. pp. 139–50. doi:10.1007/978-1-62703-026-7_9. ISBN 978-1-62703-025-0. 
  27. ↑ "A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses". Science 307 (5706): 82–86. January 2005. doi:10.1126/science.1103717. PMID 15637271. Bibcode: 2005Sci...307...82H. 
  28. ↑ "Plasmodium post-genomics: better the bug you know?". Nature Reviews. Microbiology 4 (5): 344–357. May 2006. doi:10.1038/nrmicro1392. PMID 16582929. 
  29. ↑ "A comprehensive evaluation of rodent malaria parasite genomes and gene expression". BMC Biology 12: 86. October 2014. doi:10.1186/s12915-014-0086-0. PMID 25359557. 
  30. ↑ "In vivo imaging of malaria parasites--recent advances and future directions". Current Opinion in Microbiology 8 (4): 407–414. August 2005. doi:10.1016/j.mib.2005.06.019. PMID 16019254. 
  31. ↑ "Real-time in vivo imaging of transgenic bioluminescent blood stages of rodent malaria parasites in mice". Nature Protocols 1 (1): 476–485. 2006. doi:10.1038/nprot.2006.69. PMID 17406270. 
  32. ↑ "Genetic engineering of attenuated malaria parasites for vaccination". Current Opinion in Biotechnology 23 (6): 908–916. December 2012. doi:10.1016/j.copbio.2012.04.003. PMID 22560204. 

Wikidata ☰ Q65021 entry

General information about (the biology of) P. berghei
Information about the genome and genes of P. berghei



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