Lead author Santanu Bose, a professor in WSU’s College of Veterinary Medicine, said the researchers first found evidence that the pathway was naturally activated during infection, but that the activation was not very robust. They identified the cellular factor that switches it on and then used a synthetic factor to amplify that activation. Adding recombinant ISG15 protein significantly increased cells’ resistance to infection. The resulting mechanism strengthens the cells’ own protective machinery rather than directly targeting viral components.

Technically, the study describes a non-canonical form of ISGylation mediated by integrin-FAK signaling and triggered by extracellular ISG15. ISG15 was already known to be induced internally during viral infection and had also been observed outside cells, but its extracellular function was unclear. The experiments indicate that external ISG15 can activate a previously unknown antiviral pathway, helping cells prepare for resistance before infection spreads through surrounding tissue. The approach therefore differs from an antiviral strategy that acts directly on viral proteins or other viral targets.

RSV was the principal virus used in the peer-reviewed experiments. It is a common respiratory virus that can cause severe illness in infants, older adults and people with weakened immune systems, but the reported results concern resistance in cultured epithelial cells rather than outcomes in an animal or human trial. Unpublished follow-up experiments from Bose’s laboratory, described in the WSU news release, also demonstrated antiviral activity against influenza A and parainfluenza viruses. The supplied material does not provide the methods, measurements or limitations of those unpublished results, so their scope cannot be independently evaluated from the peer-reviewed findings.

The host-directed mechanism has a potential advantage that remains to be tested broadly: mutations that alter viral targets and allow a treatment to stop working would not necessarily disrupt a strategy operating through the host cell’s own machinery. Bose said this could make the approach less vulnerable to viral mutation and potentially useful against a broad range of viruses, but the study did not demonstrate such breadth in people or in an animal model. The researchers are developing the method as a possible antiviral therapeutic, while WSU’s Innovation & Entrepreneurship team is working with them on patent protection and commercialization. That work includes an active option for a biotechnology company to explore further development.

The investigators also see possible relevance beyond infectious disease because the pathway stimulates cellular events that could be beneficial in cancer, neurological disorders and other conditions. They are exploring whether the same method of increasing pathway activation could be applied in non-infectious therapeutic settings. Those wider applications remain under investigation: the reported peer-reviewed study established increased antiviral resistance in cells, while the proposed use of recombinant ISG15 as a treatment and its possible benefits for other diseases have not been clinically established.

The project was led by graduate students Lindsay Grace Miller, who initiated the work, and Sudiksha Pandit, together with Fulbright Postdoctoral Scholar Kim Lam Chiok from Bose’s laboratory. 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. The study was supported by the National Institutes of Health and the Washington Research Foundation, and the authors declared no competing interests.

Subject of Research: Cellular signaling by extracellular ISG15 and resistance to respiratory syncytial virus

Article Title: WSU researchers discover way to ‘crank up’ the body’s antiviral defenses

Article References: WSU researchers discover way to ‘crank up’ the body’s antiviral defenses. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: ISG15, respiratory syncytial virus, antiviral signaling, host-directed defense, epithelial cells, ISGylation, integrin-FAK signaling, viral infection, experimental study, Washington State University, researchers, discover