Akalu, Y. T.; Patel, R. S.; Taft, J.; Canas-Arranz, R.; Richardson, A.; Buta, S.; Martin-Fernandez, M.; Sazeides, C.; Pearl, R. L.; Mainkar, G.; Kurland, A. P.; Geltman, R.; Rosberger, H.; Kang, D. D.; Kurian, A. A.; Kaur, K.; Altman, J.; Dong, Y.; Johnson, J. R.; Zhangi, L.; Lim, J. K.; Albrecht, R. A.; Garcia-Sastre, A.; Rosenberg, B. R.; Bogunovic, D.

Type I interferons (IFN-I) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of hundreds of IFN-I stimulated genes (ISGs), whose aggregate function results in the control of viral infection. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, self-resolving mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance. Inspired by ISG15 deficiency, we have identified a nominal collection of 10 ISGs that recapitulate the broad antiviral potential of the IFN-I system. The expression of the 10 ISG collection in an IFN-I non-responsive cell line increased cellular resistance to Zika, Vesicular Stomatitis, Influenza A (IAV), and SARS-CoV-2 viruses. A deliverable prophylactic formulation of this syndicate of 10 ISGs significantly inhibited IAV PR8 replication in vivo in mice and protected hamsters against a lethal SARS-CoV-2 challenge, suggesting its potential as a broad-spectrum antiviral against many current and future emerging viral pathogens.