HU study finds how malaria evades immune system

Discovery of parasite’s gene-hiding technique may lead to new approaches for treatment of the parasitic disease.

By JUDY SIEGEL-ITZKOVICH
Normal v genetically engineered mosquitos (photo credit: George Dimopoulos/JHU)
Normal v genetically engineered mosquitos
(photo credit: George Dimopoulos/JHU)
More than a million people – especially pregnant women and children up to the age of five – die each year of malaria, the parasitic disease caused by different strains of Plasmodium transmitted by the Anopheles mosquito.
This parasite causes the deadliest form of human malaria; its virulence is attributed to its ability to modify the infected red blood cells and to evade the immune system.
But Hebrew University of Jerusalem researchers have figured out how the most dangerous strain “tricks” the immune system, paving the way for the development of new approaches to cure this acute infection.
The research, titled “Insulator- like pairing elements regulate silencing and mutually exclusive expression in the malaria parasite Plasmodium falciparum,” was published this week in the Proceedings of the National Academy of Sciences. It was funded by the Israel Academy of Sciences and Humanities and the Einstein Kaye Fellowships, which supports outstanding research students.
Upon entering the bloodstream, the Plasmodium parasite reproduces in the red blood cells and transports its proteins to their surface.
These cells become sticky and cling to the walls of blood vessels, blocking them and damaging the human body. The immune system typically recognizes these proteins as foreign bodies and creates antibodies to fight the disease.
The deadliest of the five Plasmodium strains is Plasmodium falciparum, which causes more than 90 percent of deaths from malaria. This sophisticated strain deceives the immune system by revealing only one protein encoded by one of the 60 genes at its disposal. While the immune system is busy fighting that protein, the parasite switches to another protein not recognized by the immune system, thus avoiding the antibody response and re-establishing infection.
In research conducted at the microbiology and molecular genetics department at the Institute for Medical Research Israel-Canada and the Kuvin Center for the Study of Infectious and Tropical Diseases at the Hebrew University-Hadassah Medical School, Dr. Ron Dzikowski and research student Inbar Avraham revealed for the first time the genetic mechanism that enables a parasite to selectively express one protein while hiding other proteins from the immune system.
By combining bioinformation and genetic methods, the researchers identified a unique DNA sequence found in the regulatory regions of the gene family that encode for these surface proteins.
They showed that the parasite’s ability to express only one gene while hiding the other 59 depends on this sequence.
The research suggests that by interfering with the regulatory role of this DNA sequence, it would be possible to prevent Plasmodium falciparum from hiding most of its destructive genes from the immune system.
“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,” said Dzikowski.
“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.”