Lindsay Grace Miller, a Washington State University graduate student in Professor Santanu Bose's lab, initiated the project that identified a cellular signaling pathway researchers used to boost antiviral defenses.
Photo Credit: Washington State University
Scientific Frontline: Extended "At a Glance" Summary: Extracellular ISG15 Antiviral Pathway
The Core Concept: The extracellular ISG15 antiviral pathway is a naturally occurring cellular signaling mechanism that boosts a host cell's innate defenses to resist infection before a virus can spread.
Key Distinction/Mechanism: Unlike traditional antiviral drugs that directly target viral proteins, this host-directed approach strengthens the cell's own protective machinery via the extracellular ISG15 protein, rendering it less vulnerable to viral mutations.
Major Frameworks/Components:
- ISG15 Protein: A cellular factor naturally induced during infection that acts outside the cell as a "booster" to activate defense pathways.
- Recombinant ISG15: A synthetic protein used to artificially amplify the pathway's activation, resulting in robust cellular resistance to pathogens.
- Host-Directed Therapeutics: A treatment strategy focusing on enhancing host cellular responses rather than targeting the virus directly.
- Broad-Spectrum Efficacy: Demonstrated protective effects against respiratory syncytial virus (RSV), influenza A, and parainfluenza viruses.
Branch of Science: Virology, Cellular Biology, Immunology, Molecular Biology, and Pharmacology.
Future Application: The pathway is currently being developed for broad-spectrum antiviral therapeutics, with potential expansion into treatments for cancer, neurological disorders, and other non-infectious diseases.
Why It Matters: By fortifying the host cell rather than attacking the virus, this discovery provides a mutation-resistant strategy for combating severe respiratory illnesses and opens new avenues for treating complex cellular diseases.
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 viral infections, cancer, neurological disorders, and other diseases.
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 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,” said Santanu Bose, a professor in WSU’s College of Veterinary Medicine and the study’s lead author. “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.”
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.
Funding: The study was supported by funding from the National Institutes of Health and the Washington Research Foundation.
Published in journal: Cell Communication and Signaling
Authors: Lindsay Grace Miller, Kim Lam R. Chiok, Sudiksha Pandit, Charles Mariasoosai, Indira Mohanty, Pallavi Deol, Liyon Mehari, Michael N. Teng, Michael A. Hoffman, Sarah E. Remiker, Arthur L. Haas, Senthil Natesan, Tanya A. Miura, and Santanu Bose
Source/Credit: Washington State University | Devin Rokyta, College of Veterinary Medicine
Edited by: Scientific Frontline
Reference Number: vi102026_01
