Antigenic variation is a common feature in malaria parasites and a considerable challenge facing the development of an efficient vaccine. The expression of variant antigens on the surface of the infected red blood cell plays a role in immune evasion, sequestration and the associated pathology. There are a number of multigene families in Plasmodium that code for these variant antigens and which are targets for protective immunity. Recently, a new gene family (vir) coding for a variant surface antigen has been identified in P. vivax. Homologues of vir have now been identified in a number of other malaria parasites. Using the availability of suitable model systems, the expression of vir will be studied and the host immunity investigated. This information will then be used to establish and test a suitable approach for a vir-based malaria vaccine.
The objectives are:
1) to determine the structure of vir genes and the extent of the vir gene
repertoire in four species of Plasmodium
2) to analyse vir gene transcription in individual parasites and during the erythrocytic life cycle of the parasite
3) to determine the vir gene transcription profile during a chronic infection in four species of plasmodium
4) to locate the expression of vir in the infected erythrocyte and in other life cycle stages and to determine whether the vir proteins on viable erythrocytes are accessible to antibodies
5) to determine whether vir are immunogenic and whether the antibody response to vir alters the expression of vir in an infection or after immunisation
6) to define B and T cell epitopes of vir, and to determine whether there are responses to cross reactive or shared sequences or only to variant specific sequences
7) to determine if there is any relationship between vir expression, parasite sequestration and T cell mediated pathology. The ultimate objective is to develop a vir-based malaria vaccine.
This project will make use of the malaria sequence databases to study a family of variant antigens coded for by vir genes. It will focus on gene organisation and expression as well as the role of VIR in pathogenesis and immunity in a variety of models, and in Plasmodium vivax. This will allow a link to be established between the expression of antigenically variant vir genes and the immune response, an approach not possible in human studies. These data will enhance understanding of the feasibility of using VIR as a possible antimalarial vaccine. A comparison of vir genes and their organisation in the five species of plasmodium will be made. From this analysis, reagents will be produced to enable analysis of vir genes in the different infections. The transcription and the repertoire of vir genes expressed will be analysed, regions of the different vir genes will be cloned into expression vectors for the production of recombinant proteins, and recombinant proteins will be used to generate antibodies. Comparison of transcription and protein expression of the vir genes during the life cycle of the parasite and during the course of chronic non-lethal infections will be carried out. Since parasite proteins expressed on the surface of infected erythrocytes have been implicated in sequestration and pathology associated with plasmodium infections, transgenic parasites will be used to determine if vir genes play a role in parasite sequestration. It will be determined if the vir genes are targets of the immune response in the different infections and if the immune response to any vir gene products alters the expression of vir genes. T cell and antibody response to cross-reactive and/or variable regions of vir genes and the role of vir specific T cells in pathology of experimental cerebral malaria will be determined. Finally, recombinant proteins representing different vir genes and different regions of the molecules will be used in vaccination studies in rodent and primate infections.
1) A comprehensive catalogue of vir gene structure, organisation, expression,
possible switching rate, subcelullar location for four species of
2) Description of immunology of vir and expression pattern modulation as a result of immune pressure.
3) Description of vir protein function relating to parasite sequestration through creation of genetically manipulated Plasmodium.
4) An assessment of the vaccine or anti-disease potential of vir in animal models of malaria.
Medical Research Council (MRC);
Parasitology/National Institute for Medical Research
NW7 1AA London
Tel: +44 20 8959 3666
Fax: +44 20 8913 8593