A recent study, “An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo,” by Yemsratch Akalu, Roosheel S. Patel, Justin Taft, Rodrigo Canas-Arranz et. al., and published in Science Translational Medicine identified 10 ISGs – out of thousands of antiviral host genes – that could serve as a broad-spectrum antiviral.
Yemsratch (Macy) Akalu, Ph.D. is an Associate Research Scientist in the Laboratory of Dusan Bogunovic, Department of Pediatrics, Columbia University Medical Center. She recently took time to respond to our questions about her project.
What was the key question you addressed with this paper, and what led you to ask it?
We asked whether it is possible to mimic the natural, broad antiviral state seen in ISG15-deficient patients using a defined set of interferon-stimulated genes (ISGs). ISG15 deficiency leads to mild, persistent ISG expression and a broad resistance to viral infection. This clinical observation inspired us to test whether a minimal ISG “cocktail” could provide similar pan-viral protection without the inflammatory side effects of type I interferon.
How did the initial idea and/or observation lead to the major discovery?
The starting point was the observation that ISG15-deficient cells retain low-level ISG expression and are highly resistant to diverse viruses. From RNA-seq comparisons, we identified a subset of ISGs that remained persistently expressed and selected 10 with complementary antiviral functions. Delivering these 10 ISGs together as synthetic mRNA–LNPs recapitulated the broad-spectrum antiviral protection in cells, mice, and hamsters.
Which of your findings was the most unexpected and/or exciting to you?
The most striking result was that while individual ISGs showed only limited antiviral activity, the 10-gene combination acted synergistically to provide broad protection against multiple unrelated viruses, including influenza, Zika, and SARS-CoV-2. This demonstrated that a small, rationally designed ISG set can recapitulate the breadth and potency of the interferon response without its inflammatory downsides.
If people take away only three things from this paper, what do you want them to be?
- Natural human genetics can guide antiviral design — ISG15 deficiency revealed a safe, protective ISG state.
- A defined ISG cocktail (10 genes) can provide broad antiviral protection across multiple unrelated viruses.
- mRNA–LNP delivery is a feasible platform to translate this discovery into a potential prophylactic, though optimization of delivery, durability, and clinical application remains an important next step.
Why is this discovery of particular significance or interest to the ICIS community?
This work bridges fundamental interferon biology with translational antiviral development. For the ICIS community, it underscores a new strategy for interferon-based therapies without overt inflammation, the role of interferon-stimulated genes in human antiviral resistance, and how cytokine-inspired therapeutics can be re-imagined using mRNA technologies.
Science Translational Medicine – 13 Aug 2025 – Vol 17, Issue 811 – DOI: 10.1126/scitranslmed.adx5758
