Removing a Viral Protein Allows the Immune System to Destroy Respiratory Viruses

Eliminating the NS2 viral protein of Respiratory Syncytial Virus (RSV) helps the body to destroy the virus before it causes severe inflammation.

Respiratory viruses infect the lung cells and use them to multiply, leading to the destruction of lung cells and causing severe diseases like pneumonia or death.

However, the NS2 viral protein of Respiratory Syncytial Virus (RSV) may provide insight into stopping respiratory viruses, including the COVID-19-causing virus SARS-CoV-2, from causing an exaggerated inflammatory response in the body.

A study conducted by Washington State University and published today in MBio found that if RSV lacks the NS2 protein, the body’s immune system can destroy the virus before it causes inflammation.

In the US, RSV causes 160000 deaths a year, primarily among infants, the elderly, and immunocompromised persons. The investigators determined RSV proteins’ functions by taking each of them away. They could then identify the NS2 viral protein as an essential regulator of autophagy, a process that modulates immune defense during viral infection.

The investigators noted that NS2 interacts with and stabilizes the proautophagy mediator Beclin1, preventing its degradation by the proteasome. By studying NS2-deficient RSV, they found that NS2 contributes to RSV-mediated autophagy during infection.

“In a way you are disabling NS2’s ability to modulate the cell’s immune defense mechanism,” said Kim Choik, a post-doctoral researcher who led the WSU study. “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.”

The body fights autophagy with the cellular protein Beclin1, which attaches to smaller gene proteins. RSV’s NS2 protein hinders Beclin1, allowing the virus to replicate in the lungs. In the absence of NS2, Beclin1 can effectively destroy the virus.

This study was the first to show direct autophagy by a paramyxovirus nonstructural protein and identified a new viral mechanism for inducing autophagy. The investigators found NS2 promotes hypo-ISGylation of Beclin1, ensuring availability of active Beclin1 to engage in the autophagy process.