Decoys for misguided antibodies restore antiviral immune defense

Type I interferons are proteins released by cells in response to virus infections. They are an essential part of innate immune defenses and serve as early-warning messengers for other cells and tissues of the body. The uninfected cells prepare themselves to fight the invading virus, which ultimately limits the disease. Around 2-4% of individuals over the age of 65 years – an estimated 100 million people worldwide – have antibodies in their blood that neutralize their own type I interferons. Affected individuals with such autoantibodies cannot mount a full immune defense, making them particularly susceptible to severe viral diseases such as influenza, COVID-19, or shingles. Currently, there are no specific treatments available.

Blood samples of individuals as prerequisite

Researchers from the University of Zurich (UZH) now shed light on the molecular mechanism of how pathogenic autoantibodies recognize and inhibit type I interferons. “Our idea was to use this knowledge to create decoy molecules that bind to the autoantibodies and prevent them from inhibiting the body’s own type I interferons,” says study head Benjamin Hale, professor at the UZH Institute of Medical Virology. According to him, these decoys might form the basis for a new type of future treatment to reverse the immune defect and make affected persons less susceptible to severe infections.

First, the team consisting of scientists and clinicians analyzed blood samples from a biobank of 20 different people who had previously been identified as having autoantibodies against type I interferons, some of whom had ended up in the intensive-care unit of the University Hospital Zurich (USZ) with severe COVID-19. “Access to these biobanked samples from the University Hospital Zurich and the Swiss HIV Cohort Study was critical to the success of the study”, says first author Kevin Groen.

Decoy molecules intercept rogue antibodies

The researchers then mapped the “molecular footprints” of type I interferons – the exact regions these autoantibodies recognize on the proteins. This allowed them to create molecules in the laboratory that look like interferons from the autoantibodies’ perspective but are inactive and do not hyperstimulate the body’s immune system.

In cell culture experiments, they showed that these new molecules can be used as decoys to mop-up pathogenic autoantibodies and prevent them from blocking type I interferon. This restores the antiviral effect of type I interferon on viruses such as influenza. Furthermore, the decoy molecules can be used as agents to specifically remove pathogenic autoantibodies from blood samples, without removing other important virus-fighting antibodies. “This could ultimately lead to an application of the new decoy molecules in therapy regimens such as plasmapheresis”, says Kevin Groen.

Paving the way for future therapy

This laboratory-based work is a proof-of-concept that designed decoy molecules can successfully inhibit the pathogenic effects of type I interferon autoantibodies. “This gives us hope that a treatment to limit consequent viral disease susceptibility and severity is possible. Our results are the first steps in this direction, but further optimization is required before the decoys are ready to be tested clinically”, emphasizes Groen.