A new study by Meng Zhao and Michael T. Woodside from the University of Alberta, Canada, has revealed how the structural changes unique to the RNA of the Zika virus that helps it in evading our bodies' immune systems.
The RNAses are lytic enzymes present in living organisms, including humans, that take part in the immune response by digesting or degrading the RNA of invading viruses. The Zika virus is an RNA virus, its genome being composed of RNA. However, the cellular RNAses do not degrade the genomic RNA of the Zika virus, due a structural feature unique to it, as the team has concluded in their study.
The study conducted by the team focuses on a piece of the Zika virus' genome that exhibits 'knots' or folds which give it an ability to resist the degradation caused by the RNAses in human cells. This ability of the RNA structures, hence dubbed as exoribonuclease-resistant RNAs (xrRNAs), has been attributed to a knot-like structure in the viral genome.
The Study:
To study the knot’s mechanics of the genome, Meng Zhao and Micheal T. Woodside used optical tweezers, which rely on a laser beam to hold and move microscopic objects. The authors of the particular research article applied force to either free end of the genomic RNA strand, which allowed them to repeatedly unfold and refold the knotted conformation and observe the steps leading up to it. The study revealed that a ring shaped structure in the genome causes the resistance to RNAse, and also gives it increased mechanical stability.
The resistance to RNAse was found to be due to a knot-like structure that has extreme mechanical strength, which causes the RNAse to be physically unable to pull the viral RNA into the machinery that digests it. These unusual knot-like structures in viral exoribonuclease-resistant RNAs (xrRNAs) prevent digestion by host RNAses to create subgenomic RNAs, thereby enhancing infection and pathogenicity. It is proposed that these xrRNAs prevent digestion through mechanical resistance to unfolding.
However, the force required to unfold the structure remains unmeasured, and the factors determining RNAse resistance remain unclear. The mechanism of folding to form the knots is also not known.
(The image shows the overall process of knot formation. The knot is formed by threading the 5′ end into a three-helix junction before pseudoknot interactions closed a ring around it, as shown. The pseudoknot and tertiary contacts stabilizing the threaded 5′ end were both required to generate extreme force resistance, whereas removing a 5′-end contact produced a low-force knot lacking RNAse resistance due to the lack of resistance, causing it to be easily unwounded by RNAses.)
The formation of the folded structure involves the formation of multiple intermediates before assembling into the final RNAse-resistant knot. A strategy to then combat the virus would be to prevent the folding of the structure itself, which has been observed to be difficult. An alternative strategy, however, has been suggested by the team, to weaken the mechanical strength of the RNA knot, so that the cellular RNAses may readily degrade it.
The results of the study provide a potential target for new drug therapies to combat the Zika virus and other viruses similar to it.
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Content by Sohum Mohare
Nice info!