Author: Chris Janse
- Rodent malaria parasites as models for human malaria
- Why study rodent malaria parasites?
- Why study Plasmodium berghei?
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 human malaria. These parasites have proved to be similar to the malaria parasites 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). 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.
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 (see life cycle picture below). 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 anemia 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. These symptoms are to a certain degree comparable to symptoms of cerebral malaria in patients infected with the human malaria parasite Plasmodium falciparum.
Studies on rodent malaria parasites contributed to our knowledge on the (developmental) biology of malaria parasites
- The (ultrastructure) morphology of the different life cycle stages
- The genetics of malaria parasites
- Description of meiosis in malaria parasites
- The telomere, chromosome and genome structure of malaria parasites
- Transcriptional and translational control of gene expression
- Structure and function of malaria-specific proteins, including vaccine candidate antigens and putative drug targets
- The biology of the liver stages of malaria parasites
- Fertilization and zygote development of malaria parasites in the mosquito
A wide range of rodent malaria parasite studies have provided knowledge for developing and shaping concepts in key research areas in human malaria
- Interactions of the malaria parasite with the mosquito host and development of strategies aiming at blocking transmission 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 and vaccination approaches for malaria
- Development of novel drugs against malaria
The introduction of techniques for the in vitro cultivation of the blood stages of the most important human parasite, Plasmodium falciparum, in 1978 has greatly increased the accessibility of human parasites for studies on the biology of malaria. This has led to major research contributions using P. falciparum with direct relevance for human disease. Therefore, for studies of different aspects of human infection, one could question whether or not the use of non-human malaria parasites is still appropriate. Rodent malaria parasites and their hosts have diverged from the human malaria parasites and their host and therefore critical comparison and assessment of results from rodent malaria models is essential to assess their relevance for human disease.
Notwithstanding the advantages of studying human malaria parasites, rodent malaria parasites are still recognized as valuable model parasites for the investigation of the biology of malaria parasites, parasite-host interactions and for the development and testing of vaccines and novel drugs.
- The basic biology of rodent and human malaria parasites is highly similar
- A high level of conservation and similarity of the genome, genes and genetics exists between rodent and human parasites
- Most housekeeping genes and biochemical processes are conserved between rodent and human parasites
- The molecular basis of sensitivity and resistance of most existing antimalaria drugs show similar characteristics in rodent and human parasites
- The structure and function of many vaccine candidate 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 malaria 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 cultivation technologies for liver and mosquito stages provide tools to investigate the less accessible parts of the life cycle of the human parasites
- Efficient technologies for genetic modification are available
- Rodent parasites allow for in vivo investigation of parasite-host interactions and in vivo drug testing
- Rodent hosts with extensively characterized 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. P. berghei is an excellent model for research on the 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 of the complete genome sequence and genome organization
- Efficient methodologies for genetic modification of the parasite
- Well-characterized clones and genetically modified mutant lines, including transgenic parasites expressing reporter genes such as Green Fluorescent Protein, mCherry, OVA 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 used as a model to investigate mechanisms of drug resistance 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 analyze these parasites throughout the complete life cycle have made these two species the preferred models for analysis of Plasmodium gene function.