Fifteen years ago, immunologist Dusan Bogunovic stumbled across a handful of patients whose bodies played by different rules. They carried a rare genetic mutation that disabled an immune regulator called ISG15. The immediate downside is that they were more vulnerable to some bacterial infections. But the upside was astonishing — they seemed to be immune to every virus doctors threw at them.

These people never get the cold, flu, COVID, measles, chickenpox — you name it.

Upon closer inspection, even though these viruses didn’t make these people carrying the mutation ill, they left fingerprints in their blood.

Bogunovic, now a professor at Columbia University, soon realized that if nature had, by accident, given these patients an all-purpose viral shield, perhaps science could learn to copy it. In a new study, Bogunovic and colleagues have set out to turn this rare genetic accident into a universal antiviral — a treatment that could, in theory, protect against almost any virus, even those we have never seen before.

Mimicking an Anti-Viral Superpower

In people with ISG15 deficiency, the immune system runs a kind of constant low-grade alarm — enough to ward off viruses without burning the body in a firestorm of inflammation. It happens because the usual brakes on the immune system’s antiviral machinery never fully engage, leaving certain virus-fighting proteins active all the time.

“The type of inflammation they had was antiviral, and that’s when it dawned on me that these individuals could be hiding something,” Bogunovic said in a press release.

When Bogunovic’s team studied these patients’ cells in the lab, they found a modest but persistent activation of specific “interferon-stimulated genes” (ISGs). Out of more than 500 ISGs the body can make, the researchers identified a “syndicate” of 10 that seemed to do most of the heavy lifting. These proteins attack viruses at multiple points in their life cycle, a bit like the multi-drug regimens used to treat HIV.

To turn this discovery into a therapy, the team borrowed a trick from COVID-19 vaccines: modified messenger RNA (mRNA) packaged in lipid nanoparticles. Instead of carrying instructions for a viral spike protein, their particles deliver the genetic blueprints for those ten antiviral proteins. In cell culture, “we have yet to find a virus that can break through the therapy’s defenses,” Bogunovic says.

Testing the Idea

The approach worked in an impressive range of lab tests. In human and animal cells, the 10-ISG cocktail shut down infections from Zika, influenza, West Nile, and SARS-CoV-2 (the virus that causes COVID-19). In mice, delivering the RNA to the lungs before a flu challenge significantly reduced viral replication. In hamsters exposed to SARS-CoV-2, it reduced both lung damage and weight loss.

Crucially, the treatment didn’t shut down the rest of the immune system. Cells could still respond to interferon after being primed with the ISG cocktail, meaning it avoided the dangerous “refractory” state that can follow full-blown interferon therapy.

The protection was temporary — three to four days — but that could be enough to protect first responders, nursing home residents, or families during the opening phase of an outbreak. “We believe the technology will work even if we don’t know the identity of the virus,” Bogunovic says.

The hurdles now are engineering and delivery. Getting RNA into exactly the right tissues at high enough levels remains one of the toughest problems in biotech. But if those problems are solved, the next pandemic might be met not just with lockdowns and masks, but with a nasal spray that hands your immune system the same low-key, all-purpose viral shield that a few lucky people have had all along.

As Bogunovic puts it: “We were not looking for an antiviral when we began studying our rare patients, but the studies have inspired the potential development of a universal antiviral for everyone.”

The findings appeared in the journal Science Translational Medicine.