tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Roosheel S Patel[SUP] 1 3 4 5 [/SUP], Justin Taft[SUP] 1 2 3 4 5 [/SUP], Rodrigo Canas-Arranz[SUP] 5 [/SUP], Rachel Geltman[SUP] 1 2 3 4 5 [/SUP], Ashley Richardson[SUP] 3 4 5 [/SUP], Sofija Buta[SUP] 1 2 [/SUP], Marta Martin-Fernandez[SUP] 1 2 6 [/SUP], Christos Sazeides[SUP] 1 2 3 4 5 [/SUP], Rebecca L Pearl[SUP] 5 [/SUP], Gayatri Mainkar[SUP] 3 [/SUP], Andrew P Kurland[SUP] 2 5 7 [/SUP], Haylen Rosberger[SUP] 5 [/SUP], Diana D Kang[SUP] 3 [/SUP], Ann Anu Kurian[SUP] 3 [/SUP], Keerat Kaur[SUP] 3 [/SUP], Jennie Altman[SUP] 5 [/SUP], Yizhou Dong[SUP] 3 8 9 10 11 12 13 [/SUP], Jeffrey R Johnson[SUP] 5 7 [/SUP], Lior Zangi[SUP] 3 [/SUP], Jean K Lim[SUP] 5 [/SUP], Randy A Albrecht[SUP] 5 7 [/SUP], Adolfo García-Sastre[SUP] 5 7 11 14 15 [/SUP], Brad R Rosenberg[SUP] 5 [/SUP], Dusan Bogunovic[SUP] 1 2 16 [/SUP]
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[SUP] 1 2 [/SUP], Roosheel S Patel[SUP] 1 3 4 5 [/SUP], Justin Taft[SUP] 1 2 3 4 5 [/SUP], Rodrigo Canas-Arranz[SUP] 5 [/SUP], Rachel Geltman[SUP] 1 2 3 4 5 [/SUP], Ashley Richardson[SUP] 3 4 5 [/SUP], Sofija Buta[SUP] 1 2 [/SUP], Marta Martin-Fernandez[SUP] 1 2 6 [/SUP], Christos Sazeides[SUP] 1 2 3 4 5 [/SUP], Rebecca L Pearl[SUP] 5 [/SUP], Gayatri Mainkar[SUP] 3 [/SUP], Andrew P Kurland[SUP] 2 5 7 [/SUP], Haylen Rosberger[SUP] 5 [/SUP], Diana D Kang[SUP] 3 [/SUP], Ann Anu Kurian[SUP] 3 [/SUP], Keerat Kaur[SUP] 3 [/SUP], Jennie Altman[SUP] 5 [/SUP], Yizhou Dong[SUP] 3 8 9 10 11 12 13 [/SUP], Jeffrey R Johnson[SUP] 5 7 [/SUP], Lior Zangi[SUP] 3 [/SUP], Jean K Lim[SUP] 5 [/SUP], Randy A Albrecht[SUP] 5 7 [/SUP], Adolfo García-Sastre[SUP] 5 7 11 14 15 [/SUP], Brad R Rosenberg[SUP] 5 [/SUP], Dusan Bogunovic[SUP] 1 2 16 [/SUP]
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.