Scientists find a way to boost the body's natural viral defenses

Washington State University researchers have discovered how to "crank up" a natural defense system in the body to combat viral infection, potentially opening a new door for treating virus infections, cancer, neurological disorders and other diseases.

Published in Cell Communication and Signaling, researchers first identified the naturally occurring cellular signaling pathway responsible for activating that defense system and then discovered how to amplify its response, which significantly increased cells' resistance to infection. The method is currently under development for antiviral therapeutics, and WSU's Innovation & Entrepreneurship team in the Office of Research is working with the research team on patent protection and commercialization, including an active option to license an agreement with a biotechnology company to explore further development.

We found evidence this pathway was being activated during infection, but the activation was not very robust. We identified the cellular factor that switches it on, and when we 'artificially' cranked up that activation using a synthetic factor, it consistently protected against various viruses. Because this new pathway also stimulates critical cellular events that could be beneficial for treating cancer and neurological disorders, the discovery could have therapeutic implications well beyond infectious disease."

Santanu Bose, Professor in WSU's College of Veterinary Medicine and study's lead author

The project was led by two graduate students, Lindsay Grace Miller, who initiated the work, and Sudiksha Pandit, along with Fulbright Postdoctoral Scholar Kim Lam Chiok from Bose's laboratory.

The research focused on a protein called ISG15, which was known to be induced internally by cells during viral infection. The protein had also been observed outside cells, but its function there was not clear. Bose's team discovered that extracellular ISG15 can act as a "booster" to activate a previously unknown antiviral pathway in cells that helps prepare surrounding cells to resist infection before a virus can spread.

Researchers found the pathway is naturally activated during infection, but only at low levels. When the team artificially "cranked up" the response by adding recombinant ISG15 protein, cells were significantly more resistant to infection.

The team demonstrated the effect while studying respiratory syncytial virus, or RSV, a common respiratory virus that can cause severe illness in infants, older adults and people with weakened immune systems. Further unpublished studies from Bose's lab also demonstrated the antiviral effect of this pathway against influenza A and parainfluenza viruses.

Unlike many antiviral drugs that directly target viruses, Bose said, the newly identified mechanism works by strengthening the cell's own defenses. Because the "host-directed" therapeutic approach acts on host cells rather than viral proteins, it may be less vulnerable to the mutations that often allow viruses to evade treatments. Bose said he is hopeful the strategy could eventually have applications against a broad range of viruses.

"What makes this exciting is that we're not targeting the virus itself," Bose said. "We're helping cells activate their own protective machinery. Even if the virus mutates, this approach has the potential to remain effective because it's working through the host cell, not the virus."

While the research focused on viruses, Bose is optimistic the pathway could have therapeutic applications beyond treating virus-associated diseases. The cellular processes the new pathway influences could have great potential in treating cancer, neurological disorders and other diseases, and researchers are now exploring whether the same "cranking up" approach could be used in additional non-infectious therapeutic settings.

Professors Senthil Natesan in WSU's College of Pharmacy and Pharmaceutical Sciences and Tanya Miura in the University of Idaho's Department of Biological Sciences served as lead collaborators to the project. The study was supported by funding from National Institutes Health and Washington Research Foundation.