Asian boy using inhaler containing medicine to stop coughing
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A study of respiratory syncytial virus (RSV) has found that the viral protein NS2 may act to deter the body’s inflammatory response to respiratory viruses.

The researchers determined that if the virus lacks this protein, the human body’s immune response can destroy it before inflammation causes severe symptoms, including  pneumonia. The research, conducted at Washington State University’s (WSU) College of Veterinary Medicine, was published in the journal MBio.

Like other respiratory viruses, including the COVID-19-causing SARS-CoV-2 virus, RSV infects the lung cells responsible for exchanging gases and uses them as factories to make more viruses. Uncontrollable virus multiplication in these cells leads to their destruction and manifestation of severe inflammation; lung diseases such as pneumonia, and sometimes death.

RSV causes 160,000 deaths annually, primarily in infants, children, elderly and immune-compromised individuals, according to the National Institute of Allergy and Infectious Diseases.

“Exaggerated inflammation clogs the airways and makes breathing difficult,” said Kim Chiok, a WSU post-doctoral researcher who led the study. “This is why people who have these long-term and severe inflammatory responses get pneumonia and need help breathing, and it’s why they end up in the hospital in the ICU.”

Paramyxoviruses such as respiratory syncytial virus (RSV) are the leading cause of pneumonia in infants, the elderly, and immunocompromised individuals. Therefore, understanding host-virus interactions is essential for the development of effective interventions. 

RSV induces cell breakdown or autophagy to modulate the immune response. The viral factors and mechanisms underlying RSV-induced autophagy are little understood. But these researchers have identified  the RSV nonstructural protein NS2 as a virus component mediating RSV-induced autophagy. They show that NS2 interacts and stabilizes the proautophagy mediator Beclin1 by preventing its degradation by the proteasome. 

The research was conducted in the laboratory of Professor Santanu Bose, who is part of WSU’s Veterinary Microbiology and Pathology research unit. The researchers first determined viral proteins’ functions by using viruses lacking genes that code for different viral proteins and comparing them to a wild strain of the virus.

“The virus has a series of tools, some tools with multiple functions, we wanted to learn about these tools by essentially taking them away,” Chiok said.

Chiok identified the viral NS2 protein as a key regulator of autophagy, a cellular process that modulates immune defense during virus infection.  Autophagy is mediated by a cellular protein known as Beclin1.

When the virus enters the cell, Beclin1 can recognize and clear the threat from the cell. It does this by attaching to certain smaller gene proteins through a process known as ISGylation. It is almost like Beclin1 is putting on a suit of armor, Chiok said.

The study showed that RSV’s NS2 protein removes this “armor” from Beclin1 which allows the virus to persist and replicate within the cell, spreading to other cells and causing damage that initiates an exaggerated inflammatory response from the body that culminates in airway diseases like pneumonia. Without the NS2 protein, the virus is routinely destroyed by Beclin1.

“In a way you are disabling NS2’s ability to modulate the cell’s immune defense mechanism,” Chiok said. “You can use therapeutics to target that protein, and potentially transfer this concept to other respiratory viruses like influenza A virus and SARS-CoV-2.”

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