AbstractMalaria has afflicted man for thousands of years and still affects millions ofpeople each year. A frequently fatal complication of infection with Plasmodiumfalciparum is cerebral malaria, which is associated with the cytoadherence of infected erythrocytes to the endothelial lining of capillaries and venules of the brain. A complete understanding of the mechanisms of cytoadherence is yet to be gained, with a long term view to developing drugs which may block or reverse the interaction.
While in the blood stages, the parasite expresses a diverse range of variants ofthe var antigen, encoded by var genes on the surface of infected erythrocytes. Rapid switching between different variants allows the parasite to evade the host immune response and hence, splenic clearance.
Recently, Ockenhouse and colleagues identified a distinct antigen of P. falciparum which they named 'sequestrin'. Sequestrin binds to CD36, a receptorfound on endothelial cells. In an independent series of studies in our laboratory, a locus important in binding to CD36 has been mapped to chromosome 9. Hence, the evidence suggests that the sequestrin gene is the locus located on chromosome 9.
In the work described here, mapping studies have shown that the sequestringene is not located on chromosome 9. It is located on a smaller chromosome, possibly chromosome 4 of the parasite. Prior to the start of this project, only —2kb of the —6kb gene had been sequenced. In the course of this project, a further 256bp of the gene has been sequenced. Analysis of repeat sequences within the known sequence has been carried out on 10 isolates and clones of P. falciparum, showing size variation similar to that commonly associated with other malarial antigens, where most mutations obtained e.g. amino acid deletions or base chages, were silent. Transfection experiments are underway to elucidate the biological function of the protein by "knocking out" the sequestrin gene. Should transfections prove successful, it should be possible to establish with certainty whether this gene mediates binding to CD36. If so, it would be an ideal vaccine candidate and may be useful in producing anti-idiotype antibodies for immunotherapy of cerebral and severe P. falciparum malaria.
|Date of Award||Oct 1996|
|Supervisor||Karen Gibb (Supervisor)|