Discrete DNA Elements Regulate the Expression of Malaria Parasite Antigens

Molecular biologists studying how the protozoan parasite Plasmodium falciparum, which causes more than 90% of deaths associated with malaria, evades human immune attack through antigenic variation have found that this process is regulated by discrete DNA elements located in the var genes.

Individual parasites express only a single var gene at a time, maintaining the remaining var genes in a transcriptionally silent state. Strict pairing between var gene promoters and a second promoter within an intron found in each var gene is required for silencing and counting of var genes by the mechanism that controls mutually exclusive expression.

Investigators at the Hebrew University of Jerusalem (Israel) outlined how this mechanism works in a paper that was published in the November 29, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America.

They reported that the approximately 60 var genes were expressed one at a time while the others were silenced. The selectivity of gene expression was accomplished by discrete insulator-like DNA elements that were required for pairing var promoters and introns. These elements were found to be essential for regulating silencing and mutually exclusive gene expression. These elements, found in the regulatory regions of each var gene, were bound by distinct nuclear protein complexes. Any alteration in the specific, paired structure of these elements by either deletion or insertion of additional elements resulted in an unregulated var gene.

Senior author Dr. Ron Dzikowski, senior lecturer in microbiology and molecular genetics at the Hebrew University of Jerusalem, said, "These results are a major breakthrough in understanding the parasite's ability to cause damage. This understanding could lead to strategies for disrupting this ability and giving the immune system an opportunity to clear the infection and overcome the disease. This clever parasite knows how to switch masks to evade an immune attack, but our discovery could lead to new ways to prevent it from continuing this dangerous game."

Related Links:
Hebrew University of Jerusalem