Olitzki Prize
IMMUNE EVASION THROUGH ANTIGENIC VARIATION BY MALARIA PARASITES

The virulence of Plasmodium falciparum, the causative agent of the deadliest form of human malaria is attributed for its ability to evade human immunity through antigenic variation. These parasites alternate between expression of variable antigens, encoded by members of a multi-copy gene family named var. Immune evasion through antigenic variation depends on tight regulation of var gene expression ensuring that only a single var gene is expressed at a time while the rest of the family is maintained transcriptionally silent. The mechanisms that regulate mutually exclusive expression remains one of the biggest mysteries in eukaryotic gene expression. We found that repression of the entire gene family is mediated by insulator-like DNA elements that enable a long distance silencer to silence all var promoters by default. These insulators were shown to binds specific but yet unknown nuclear proteins. In addition, we showed that activation of the single var gene expressed is mediated by antisense lncRNA molecule transcribed from that var intron. We were able to activate a silent var gene by expressing its antisense lncRNA and down regulate an active one by interfering with its particular lncRNA. I will discuss the interplay between the mechanisms that repress the entire var gene family and the mechanisms of the choice of singular gene activation that underlie mutually exclusive expression.