Gene Silencing Masks the Malaria Parasite

Researchers have identified a mechanism used by the malaria parasite Plasmodium falciparum to regulate the var gene responsible for the manufacture of the variable surface protein PfEMP1, which hides the parasite from the host's immune response. While the P falciparum genome contains at least 50 var genes, only one is expressed at any given time, giving rise to a single version of the PfEMP1 protein.

Investigators at The Walter and Eliza Hall Institute of Medical Research (Melbourne, Australia) studied the region around the var gene by inserting a gene for drug resistance adjacent to it. They reported in the April 8, 2005, issue of Cell that a process of gene silencing was operating. In some parasites, the DNA region was active, and the parasites showed resistance to the drug. In others, the drug killed the parasites.

Gene silencing suggested the involvement SIR2 (silent information regulator 2) protein, which was known to play a role in gene silencing in yeast by modifying gene packaging. To learn what SIR2 was doing, the investigators developed a parasite line that lacked the SIR2 gene. "Silencing occurs by packaging up the DNA into a tight form and preventing it from being expressed. That tight packaging involves SIR2,” said senior author Dr. Alan Cowman, professor of infection and immunity at The Walter and Eliza Hall Institute of Medical Research.

Another potential control mechanism for gene silencing is compartmentalization. The investigators used fluorescence in situ hybridization (FISH), a technique that employs fluorescent-labeled probes specific for particular segments of DNA, to determine the position of var genes in "on” and "off” states. They found that there appeared to be discrete nuclear compartments that allowed gene expression to occur. When a var gene moved into this compartment, it became activated and its version of PfEMP1 was expressed.