Hebrew University develops ‘breakthough’ method to suppress malaria parasite’s harmful genes

Jerusalem researchers have discovered the genetic mechanism by which the 'Plasmodium falciparum' parasite evades the body’s immune response to cause the most dangerous type of human malaria.

By JUDY SIEGEL-ITZKOVICH
Prof. Ron Dzikowski and PhD student Inbar Amit-Avraham (photo credit: HEBREW UNIVERSITY)
Prof. Ron Dzikowski and PhD student Inbar Amit-Avraham
(photo credit: HEBREW UNIVERSITY)
Jerusalem researchers have discovered the genetic mechanism by which the Plasmodium falciparum parasite evades the body’s immune response to cause the most dangerous type of human malaria.
The study, by Hebrew University Faculty of Medicine Prof. Ron Dzikowski and his doctoral student Inbar Amit-Avraham, has just been published in the Proceedings of the National Academy of Sciences (PNAS). They conducted their study at the microbiology and molecular genetics department at the Institute for Medical Research Israel-Canada and at the medical school’s Sanford Kuvin Center for the Study of Infectious and Tropical Diseases.
As many as a million people in the Third World – mostly pregnant woman and young children – are killed annually by the parasite, which replicates in the circulating blood of infected individuals and modifies the surface of infected red blood cells. Its virulence comes from its impressive ability to hide from the immune system by selectively changing which surface proteins it displays, said Dzikowski.
This sophisticated game of hide-and-seek involves continually alternating foreign molecules called antigens. This can trigger an immune response called antigenic variation.
Previous research has found that the antigens that the parasite selectively displays are encoded by members of a gene family named var. The parasite tightly regulates the expression of these var genes so that only one is expressed at any given time, while the rest of the family is maintained silent.
Understanding this complex mechanism is essential to understanding how the deadly Plasmodium falciparum parasite evades the immune system. It is also more broadly important to science because the process by which cells can express a single gene while keeping alternative genes silent is one of the unsolved mysteries in the field of eukaryotic gene expression.
The researchers found that at the precise moment in the cell cycle when a specific var gene is active, corresponding RNA molecules (of a type called long non-coding RNA) are present. These long noncoding RNA (lncRNAs) molecules incorporate themselves into DNA structures, and determine how the parasite selects a single gene for expression while the rest of the family is kept silent. In a series of genetic experiments in transgenic parasite lines, the researchers were able to activate silent var genes by expressing their specific lncRNAs molecules.
In collaboration with Dr.
Eylon Yavin of the HU’S School of Pharmacy Institute for Drug Research, the researchers developed a novel way to interfere with these lncRNAs and showed that through this interference, they could suppress the active var gene and induce switching toward expression of other var genes. Thus, they showed that the lncRNAs molecules play a key role in regulating the genetic mechanisms enabling the deadly parasite to evade human immunity.
Dzikowski concluded: “We believe this breakthrough has exposed the tip of the iceberg in understanding how the deadliest malaria parasite regulates the selective expression of its genes, enabling it to evade the immune system.
Understanding the mechanisms by which the parasite evades immunity takes us closer to finding ways to either block this ability, or force the parasite to expose its entire antigenic repertoire and thus allow the human immune system to overcome the disease.
Such findings can help pave the way for development of new therapies and vaccines for malaria.”