- Rodent malaria parasites as models for human malaria
- Why study rodent malaria parasites?
- Why study Plasmodium berghei?
Author: Chris Janse
Plasmodium berghei is one of the many species of malaria parasites that infect mammals other than humans. P.berghei is one of the four species that have been described in murine rodents of West Africa. The rodent parasites are not of direct practical concern to man or his domestic animals. The interest of rodent malaria parasites is that they are practical models for the experimental study of mammalian malaria. These parasites have proved to be analogous to the malarias of man and other primates in most essential aspects of structure, physiology and life cycle (Carter and Diggs 1977. In: 'Parasitic Protozoa', vol.3 pp.359-465. Academic Press, New York).
Studies on rodent malaria parasites contributed to our knowledge on the developmental biology of malaria parasites in general
- (Ultra-structural) morphology of the different life cycle stages
- Genetics of malaria parasites
- Description of meiosis in malaria parasites
- Telomere, chromosome and genome structure of malaria parasites
- Function/structure of malaria specific proteins, including vaccine candidate antigens
- Biology of the liver stages of malaria parasites
- Fertilization and zygote development of malaria parasites in the mosquito
A wide range of investigations using rodent parasites have provided knowledge for developing and shaping concepts in major areas of research on the human disease
- Interactions of the malaria parasite with the mosquito host and development of strategies that block transmisson by the mosquito
- Antigenic variation and diversity of blood stage parasites
- Immunity to malaria
- Development of drug resistance in malaria parasites and mechanisms of drug resistance
- Development of vaccines/vaccination approaches for malaria
- Development of drugs against malaria
The introduction of techniques for the in vitro cultivation of the blood stages of most important human parasite, Plasmodium falciparum, in 1978 has greatly increased the accessibility of human parasites for studies on the biology of malaria.
This development of cultivation technology has led to major research contributions using P. falciparum with direct relevance for human disease. Therefore, for investigation of different aspects of human infection one could question whether or not the use of non-human malaria parasites is still appropriate. Rodent parasites and their hosts are diverged from the human parasites and human host and therefore careful comparison and assessment of results from rodent models is essential to assess their relevance for human disease.
Notwithstanding the advantages of studying human malaria parasites, rodent parasites are recognised as valuable model parasites for the investigation of the developmental biology of malaria parasites, parasite-host interactions, vaccine development and drug testing.
- The basic biology of rodent and human parasites is similar
- The genome organisation and genetics is conserved between rodent and human parasites
- Housekeeping genes and biochemical processes are conserved between rodent and human parasites
- The molecular basis of drug-sensitivity and resistance show similar characteristics in rodent and human parasites
- The structure and function of vaccine candidate target antigens are conserved between rodent and human parasites (for example TRAP and CSP of sporozoites; CTRP, P25 and P28 of ookinetes; AMA1 and MSP1 of merozoites; P45/48, P47 and P230 of gametes)
- The manipulation of the complete life-cycle of rodent parasites, including mosquito infections is simple and safe
- In vitro culture techniques for large-scale production and manipulation of different life-cycle stages are available. For example, in vitro cultures of liver and mosquito stages provide tools to investigate the less accessible parts of the life cycle of the human parasites
- Methodologies for genetic modification are available
- Rodent parasites allow in vivo investigations of parasite-host interactions and in vivo drug testing
- Rodent hosts with extensively characterised genetic backgrounds and transgenic lines are valuable and available tools for immunological studies
We describe here in more detail the malaria parasite Plasmodium berghei, which is one of the four rodent parasites that infect African murine rodents. The emphasis is on the developmental biology of this parasite and on our research in Leiden.
P. berghei is an excellent model for research on the developmental biology of malaria parasites, because of the availability of:
- Technologies for in vitro cultivation and large scale production and purification of the different life cycle stages
- Knowledge on the genome sequence and organisation
- Methodologies for genetic modification of the parasite
- Well characterised clones and genetically modified mutant lines, including transgenic parasites expressing reporter genes such as Green Fluorescent Protein, mCherry and Luciferase.
Rodent malaria parasites (RMP) are used extensively as models of human malaria. Four different species that infect African rodents have been adapted for laboratory use: Plasmodium berghei, P. yoelii, P. chabaudi and P. vinckei. Small differences exist in the biology of the different RMP in laboratory mice and this makes them particularly attractive models to investigate different aspects of human malaria. Specifically, P. chabaudi is a model to investigate mechanisms of drug resistances and immune evasion, in particular antigenic variation. It invades normocytes and reticulocytes and mostly produces chronic, non-lethal, infections. In contrast, P. berghei preferentially invades reticulocytes and usually produces infections in mice that induce severe pathology. In combination with different mouse strains it has been used as a model to study immunopathology, experimental cerebral malaria, pregnancy-associated malaria and lung pathology. P. yoelii is widely used in studies on the biology of liver stages and on innate and acquired immunity against liver stages. Blood stage P. yoelii parasites of some lines are restricted to reticulocytes whereas others can invade all red blood cells and have been used to study receptors for erythrocyte binding. The availability of efficient reverse genetics technologies for P. berghei and P. yoelii and the ability to analyse these parasites throughout the complete life cycle have made these two species the preferred models for analysis of Plasmodium gene function.
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