Revealed: how malaria evades the immune response by using long noncoding RNA to express one gene while silencing others
Up to one million people - mainly pregnant woman and young children - are killed each year by the Plasmodium falciparum parasite, which causes the most devastating form of human malaria.
Now, researchers at the Hebrew University of Jerusalem have revealed the genetic trickery this deadly parasite deploys to escape attack by the human immune system.
The parasite is known to replicate within the circulating blood of infected individuals and modify 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.
This sophisticated game of hide-and-seek, which involves continually alternating the foreign molecules, called antigens, that can trigger an immune response, is called antigenic variation.
Previous research has shown that the antigens 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.
In research at the Hebrew University’s Faculty of Medicine, Prof. Ron Dzikowski and his PhD student Inbar Amit-Avraham 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 noncoding RNA) are present.
Furthermore, 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, thus demonstrating their functional role in var gene activation.
The research was conducted at the Department of Microbiology and Molecular Genetics at the Institute for Medical Research Israel-Canada, in the Hebrew University’s Faculty of Medicine; and at the Sanford F. Kuvin Center for the Study of Infectious and Tropical Diseases at the Hebrew University-Hadassah Medical School.
In a further development, the researchers collaborated with Dr. Eylon Yavin, at the Institute for Drug Research in the Hebrew University’s School of Pharmacy, to develop a novel way to interfere with these lncRNAs. They further showed that through this interference they could suppress the active var gene, erase the memory that regulates var expression, and induce switching towards expression of other var genes.
The research provides evidence that these lncRNAs molecules play a key role in regulating the genetic mechanisms enabling the deadly parasite to evade human immunity.
According to Prof. Dzikowski, “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.”
The study appears in the Proceedings of the National Academy of Sciences (PNAS Early Edition) as Amit-Avraham et al., “Antisense long noncoding RNAs regulate var gene activation in the malaria parasite Plasmodium falciparum” ( www.pnas.org/cgi/doi/10.1073/pnas.1420855112 ).
The research was supported by Israel Academy of Science and Humanities and European Research Council. Inbar Amit-Avraham was supported by the Abisch–Frenkel Foundation.
For information or interviews, contact:
Hebrew University Foreign Press Liaison
+972-2-5882844 / +972-54-8820860
Dov Smith | Hebrew University
Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System
Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
22.08.2017 | Health and Medicine
22.08.2017 | Materials Sciences
22.08.2017 | Life Sciences