4. May 2021
“Viruses, creatures on the edge between living and non-living organisms, possess an evil genius that never ceases to amaze me,” says Dominik Hrebik, first author of a recently published study that reveals the astonishing behaviour of rhinoviruses. Dominik Hrebik, a PhD student from Pavel Plevka’s research group, is studying the three-dimensional atomic structures of viruses with the help of cryo-electron microscopy. This technology helped him to discover how rhinoviruses attack human cells, and his findings disproved a current hypothesis linking low pH to genome release within the cell. His study was published in the April issue of Proceedings of the National Academy of Sciences of the United States of America (PNAS).
Rhinoviruses are among the most common causes of infections in mankind, causing the common cold and other respiratory illnesses. They are present worldwide and symptoms include sore throat, runny nose, nasal congestion, sneezing and cough. Although common colds are of little direct medical consequence, they are associated with enormous cost to society in the form of missed school and work and unnecessary medical care. They also exacerbate asthma symptoms.
To infect a human, the rhinovirus binds to a human cell protein called Intercellular Adhesion Molecule-1, or ICAM-1 for short, and anchors itself to the cell’s surface. Afterward, ICAM-1 sends a signal to the cell, which makes the cell swallow the virus. When the virus enters the cell, it releases its genome to finally take over the human cell replication machinery and to start producing new viruses. The virus genome pops inside the cell like a balloon filled with water. Rhinoviruses are uninvited guests delivering a nasty surprise to the human cells.
Until now, it has not been clear how the virus binds to the receptor, and what exactly triggers the genome release. Therefore, the research team decided to observe these events under a cryo-electron microscope, which would reveal the process in atomic detail. “I noticed that after binding to the ICAM-1 protein, the virus changes the structure of its protein shell and RNA genome, which wasn’t observed before. As we later found out, this step is crucial for subsequent genome release,” explains Dominik Hrebik.
The previous state of knowledge has indicated that low pH induces genome release inside the cell. Thus, the researchers tried to repeat the experiments and exposed the virus to acidic pH. However, nothing happened. The virus did not react at all. Therefore, they concluded that something else is needed to induce the genome release.
“After looking at the structure of the virus-receptor complex, I proposed a mechanism where ICAM-1 in combination with acidic pH induces the release of the RNA from the virus. To confirm my theory, I tried another experiment where I formed a virus-receptor complex which was subsequently exposed to acidic pH. When I put the sample into the cryo-electron microscope, I could immediately see that the experiment was successful. Almost all viruses released their genome,” says Dominik Hrebik. The experiments conducted by the research team verified Hrebik´s theory that the receptor plays a crucial role in the genome release – a fact that was unknown until now. This new discovery could lead to new antiviral therapeutics, which would block the formation of the virus-receptor complex, or the release of the genome inside the cell.
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