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Sci Transl Med
. 2025 Aug 13;17(811):eadx5758.
doi: 10.1126/scitranslmed.adx5758. Epub 2025 Aug 13. An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo
Yemsratch T Akalu 1 2 , Roosheel S Patel 1 3 4 5 , Justin Taft 1 2 3 4 5 , Rodrigo Canas-Arranz 5 , Rachel Geltman 1 2 3 4 5 , Ashley Richardson 3 4 5 , Sofija Buta 1 2 , Marta Martin-Fernandez 1 2 6 , Christos Sazeides 1 2 3 4 5 , Rebecca L Pearl 5 , Gayatri Mainkar 3 , Andrew P Kurland 2 5 7 , Haylen Rosberger 5 , Diana D Kang 3 , Ann Anu Kurian 3 , Keerat Kaur 3 , Jennie Altman 5 , Yizhou Dong 3 8 9 10 11 12 13 , Jeffrey R Johnson 5 7 , Lior Zangi 3 , Jean K Lim 5 , Randy A Albrecht 5 7 , Adolfo García-Sastre 5 7 11 14 15 , Brad R Rosenberg 5 , Dusan Bogunovic 1 2 16
Affiliations
Type I interferons (IFN-Is) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of thousands of IFN-I-stimulated genes (ISGs), whose aggregate function results in the control of viral infections. 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, often 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 the antiviral state of humans with ISG15 deficiency, we identified a nominal collection of 10 ISGs that recapitulated the broad antiviral potential of the IFN-I system, which typically induces the expression of thousands of ISGs. The expression of this 10-ISG collection in an IFN-I-nonresponsive cell line increased cellular resistance to Zika virus, vesicular stomatitis virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A lipid nanoparticle-encapsulated messenger RNA (mRNA) formulation of this 10-ISG collection reduced influenza A virus plaque size in samples collected from infected mice when given prophylactically. Moreover, when used collectively and delivered prophylactically, the 10-ISG collection was able to protect hamsters against a lethal SARS-CoV-2 challenge, in contrast with the lack of efficacy when mRNAs were delivered individually. These findings suggest that these 10 ISGs have potential as a broad-spectrum antiviral prophylactic.
. 2025 Aug 13;17(811):eadx5758.
doi: 10.1126/scitranslmed.adx5758. Epub 2025 Aug 13. An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo
Yemsratch T Akalu 1 2 , Roosheel S Patel 1 3 4 5 , Justin Taft 1 2 3 4 5 , Rodrigo Canas-Arranz 5 , Rachel Geltman 1 2 3 4 5 , Ashley Richardson 3 4 5 , Sofija Buta 1 2 , Marta Martin-Fernandez 1 2 6 , Christos Sazeides 1 2 3 4 5 , Rebecca L Pearl 5 , Gayatri Mainkar 3 , Andrew P Kurland 2 5 7 , Haylen Rosberger 5 , Diana D Kang 3 , Ann Anu Kurian 3 , Keerat Kaur 3 , Jennie Altman 5 , Yizhou Dong 3 8 9 10 11 12 13 , Jeffrey R Johnson 5 7 , Lior Zangi 3 , Jean K Lim 5 , Randy A Albrecht 5 7 , Adolfo García-Sastre 5 7 11 14 15 , Brad R Rosenberg 5 , Dusan Bogunovic 1 2 16
Affiliations
- PMID: 40802739
- DOI: 10.1126/scitranslmed.adx5758
Type I interferons (IFN-Is) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of thousands of IFN-I-stimulated genes (ISGs), whose aggregate function results in the control of viral infections. 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, often 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 the antiviral state of humans with ISG15 deficiency, we identified a nominal collection of 10 ISGs that recapitulated the broad antiviral potential of the IFN-I system, which typically induces the expression of thousands of ISGs. The expression of this 10-ISG collection in an IFN-I-nonresponsive cell line increased cellular resistance to Zika virus, vesicular stomatitis virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A lipid nanoparticle-encapsulated messenger RNA (mRNA) formulation of this 10-ISG collection reduced influenza A virus plaque size in samples collected from infected mice when given prophylactically. Moreover, when used collectively and delivered prophylactically, the 10-ISG collection was able to protect hamsters against a lethal SARS-CoV-2 challenge, in contrast with the lack of efficacy when mRNAs were delivered individually. These findings suggest that these 10 ISGs have potential as a broad-spectrum antiviral prophylactic.