Molecular mechanisms of antigenic variation in malaria parasites.

摘要

The var multigene family encodes proteins that are responsible for antigenic variation and cytoadherence of the malaria parasite Plasmodium falciparum. These genes are subject to strict mutually exclusive expression leading to silencing of all but one gene. Transcriptional switches lead to changes in antigenic properties allowing these parasites to avoid the immune response. Little is known about how this is coordinated at the molecular level. This work investigates three aspects of var gene expression. First, the rates of transcriptional switching are quantified and described. There is no pre-determined order in which genes are expressed but switching rates vary between genes with different chromosomal locations. Second, the role of var introns in regulating transcriptional silencing is examined. Introns are shown to silence var transcription in chromosomally integrated transgenes in a manner that suggests specific interactions between individual var promoters and introns. Finally, a novel post-transcriptional regulatory mechanism is described for a particular var gene implicated in pregnancy-associated malaria. var2csa translation is shown to be repressed by a small upstream open reading frame that potentially forms the basis of a genetic switch to selectively express this gene only in the presence of the appropriate host tissue.