Viral diseases are a major driver of illness and death for millions around the world. The 1918 influenza pandemic killed between 20 million and 50 million people in Europe alone, with similar numbers elsewhere. A century later, flu viruses still hospitalize about half a million people every year and kill tens of thousands.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has killed an estimated 10 million to 15 million people and is not fully over. Climate change and the destruction of natural habitats will likely expose us to new viral diseases whose impact we cannot yet predict. A promising approach for future preparedness is to develop broad antiviral treatments that can target as many types of viruses as possible, including ones we have not yet encountered.
Type 1 interferons are proteins that occur naturally in the body and are produced during a viral attack. They play several roles in viral illness, including signaling to other cells that the body is under attack. Those cells then shift into a state of heightened readiness that helps them better respond to invading viruses. This readiness process is mediated by additional proteins activated by the interferons.
That state comes with a cost, similar to the cost of staying prepared for war in the real world. In the body this response is called inflammation, and it has many unwanted side effects. That is one reason interferons alone have not been especially successful as a medical treatment.
Two key proteins involved in the processes triggered by type 1 interferon are USP18 and ISG15. Both are central to dampening the antiviral response produced by interferons. Their absence can be dangerous and can lead to severe inflammation and autoimmune disease. A lack of USP18 causes reactions so severe they can be fatal. A lack of ISG15, however, produces a milder reaction, which has been documented in 10 families around the world who carry this mutation. In lab conditions, fibroblasts taken from individuals missing ISG15 showed strong resistance to deliberate viral infections compared with control cells.
The ISG15 clue
About 15 years ago, Dusan Bogunovic, an immunologist at Columbia University, noticed a surprising pattern: several of his patients who had persistent bacterial infections and struggled to fight them off showed an inflammatory reaction typically associated with viral illness. Bogunovic discovered that all of them lacked the regulatory protein ISG15.
Without ISG15, roughly 60 different proteins accumulate inside the patient’s cells. These proteins are also linked to the interferon response and ultimately drive the strong resistance to viral disease. When researchers explored how to apply this insight, they understood that deliberately disabling the ISG15 gene in patients would be too dangerous. Instead, they examined the other 60 proteins and selected several candidates for a new experimental therapy, which has shown promising early results in mice and hamsters, the latter considered a better model for viral infection.
After a careful screening process, Bogunovic and his team narrowed the list to 10 proteins. They packaged the mRNA that encodes these proteins inside lipid nanoparticles, similar to the technology used in COVID vaccines. The nanoparticles were delivered through nasal drops into the lungs of mice and hamsters. Once inside lung cells, the particles began producing the 10 proteins, triggering a low-level antiviral inflammatory response. Although much milder than the inflammation caused by ISG15 deficiency, it was strong enough to suppress the replication of influenza and coronavirus model viruses and significantly reduced the severity of illness for three to four days compared with control groups.
This research is still at a very early stage. Its path to clinical use will be long and will require extensive testing for both effectiveness and safety. So far, the treatment has been tested only in the lungs of rodents, but viral diseases often affect other organs, so the delivery method itself will need to be adapted.
The researchers propose that this treatment could eventually serve as an early intervention during outbreaks of known viral diseases, such as flu or HIV/AIDS, as well as new ones like COVID-19. If successful, it could become a valuable addition to today’s limited and highly virus-specific antiviral therapies.