General introduction P. berghei model

• Rodent malaria parasites as models for human malaria
• Why study rodent parasites?
• Why study Plasmodium berghei?

Rodent malaria parasites as models for human malaria

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).

Examples are:

• (Ultra-structural) morphology of the different life cycle stages
  Sinden, R.E. (1978) Cell Biology In: Rodent Malaria (R. Killick-Kendrick and W. Peters, eds.) pp 1-52.Academic Press, London; Aikawa, M. and Seed T.M. (1980). Morphology of Plasmodia. In: Malaria (Kreier, J.P. ed.) Volume 1, pp. 285-345. Academic Press. New York.
• Genetics of malaria parasites
  Walliker et al. (1971) Nature 232; 561-2; Walliker (1983) Adv. Parasitol 22, 217-59.
• Description of meiosis
  Sinden, R.E. and Hartley R.H. (1985) J. Protozool. 32, 742-4; Janse C.J. et al. (1986) Mol. Biochem. Parasitol. 20, 173-182.
• Telomere, chromosome and genome structure of malaria parasites
  Ponzi M. et al. (1985) EMBO J, 4, 2991-2995, Janse C.J. (1993) Parasitol. Today 9, 19-22; Pace et al. (2000) Genome Res. 10, 1414-20; van Lin, L.H.M. et al. (2001). Int. J. Parasitol. 30, 357-370; van Lin, L.M.H. et al. (2001) Nucleic Acids Res. 29, 2059-68. Carlton J.M. et al. (2002). Nature 419: 512-9
• Function/structure of malaria specific proteins, including vaccine candidate antigens
  Menard, R. et al. (1997) Nature 385, 336-40; Sultan A.A., et al. (1997) Cell. 90: 511-22; Dessens, J.T. et al. (1999) EMBO J.18, 6221-7; Wengelnik, K. et al. (1999) EMBO J. 18,5195-204; Kocken, C. et al (1998) J Biol Chem. 273, 15119-24; van Dijk, M.R. et al. (2001) Cell 104:153-64. Tomas A.M. et al. (2001) EMBO J. 20: 3975-83, Matuschewski K. et al. (2002) EMBO J. 21: 1597-606
• Biology of the liver stages
  Meis, J.F. et al. (1983) Nature 302,424-6; Sinnis, P. (1996) Infect Agents Dis 5:182-9; Mota, M.M. et al. (2001) Science 291, 141-4; Mota, M.M. et al. (2002) Nat. Med. 8: 1318-22; Carrolo M. et al. (2003) Nat. Med. 9, 1363-9
• Fertilization and zygote development in the mosquito
  Yuda, M. et al. (1999) J Exp Med. 189, 1947-52; Billker, O. et al., (1998) Nature 392, 289-92; Paul, R.E. et al. (2000) Science 287, 128-31; van Dijk, M.R. et al. (2001) Cell 104:153-64; Siden-Kiamos, I. et al. (2000) J Cell Sci.113, 3419-26; Billker, O et al. (2004) Cell 117, 503-514
• Biology of the developmentally regulated ribosomes
  Gunderson, J.H. et al. (1987) Science 238, 933-7; Spaendonk, R.M et al. (2001) J Biol Chem. 276, 22638-47.

Examples are:

• Parasite-host interactions in the mosquito
  Sinden, R.E. (1996 ) Adv Parasitol. 38:53-117, Han, Y.S. et al (2000) EMBO J. 19: 6030-40; Dimopoulos, G. et al. (2001) Curr Opin Immunol. 13, 79-88; Blandin S. et al. (2004) Cell 116: 661-70; Osta M.A. et al. (2004) Science 303: 2030-2 .
• Antigenic variation of blood stage parasites
  Philips, R.S. et al. (1997) Parasit. Immunol. 19, 427-34; Preiser, P.R. et al. (1999) Nature 398, 618-622; Janssen, C. et al. (2002) Proc R Soc Lond B Biol Sci. 269: 431-6; Carlton J.M. et al. (2002) Nature 419: 512-9.
• Immunity to malaria
  Langhorne, J. (1994). Immunol. Lett. 41, 99-102; Jakobsen P.H. et al., (1995) Parasit. Immunol. 17, 223-231, Doolan, D.L. and Hoffman S.L. (1997) Philos. Trans. R. Soc. Lond. B. Biol. Sci 352, 1361-7; Ocana-Morgren, C. at al. (2003) J. Exp. Med. 197, 143-51.
• Vaccine development
  Nussenzweig, V. and Nussenzweig, R.S. (1989) Adv Immunol. 1989;45:283-334; Nardin E.H. and Nussenzweig, R.S. (1993) Annu Rev Immunol.11, 687-727; Hoffman, S.L. (1997) Immunol Cell Biol. 75, 376-81; Krzych, U. et al. (2000) Immunol. Rev. 174,123-34.
• Drug development and drug resistance
  Peters, W. (1987) Chemotherapy and drug resistance in malaria, vol. 1 & 2 (second edition), Academic Press, London; Peters, W. (1998) Adv Parasitol. 1998;41:1-62; Carlton, J. (2001) Trends in Parasitol. 17, 209-252.

Why study rodent parasites?

The introduction of techniques for the in vitro cultivation of the blood stages of most important human parasite, P. 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. Examples are studies on the molecular basis of drug resistance, antigenic variation and sequestration, mechanisms of erythrocyte invasion and protein trafficking and investigations on the plastid organelle. 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.
Why?

• 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 lifecycle 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

Why study Plasmodium berghei?

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 and Luciferase.

The other rodent parasites are invaluable in different areas of malaria research. For example, P. chabaudi is recognised as a useful model for investigations of mechanisms of drug resistance and antigenic variation. This parasite shows antigenic variation during long lasting, non-lethal, infections in laboratory rodents. In contrast, P. berghei infections are usually rapidly lethal to laboratory rodents which hampers studies on the in vivo generation and selection of antigenic variants. Another example is P. yoelii, which is extensively used in studies on the biology of liver stage and blood stage antigens and their role in immunity and vaccine development.

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