2025-08-13 コロンビア大学
<関連情報>
- https://www.cuimc.columbia.edu/news/one-universal-antiviral-rule-them-all
- https://www.science.org/doi/10.1126/scitranslmed.adx5758
SG15欠損にインスパイアされたmRNAベースの広域抗ウイルス剤は、in vitroおよびin vivoでウイルス感染から保護する An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo
Yemsratch T. Akalu, Roosheel S. Patel, Justin Taft, Rodrigo Canas-Arranz, […] , and Dusan Bogunovic
Science Translational Medicine Published:13 Aug 2025
DOI:https://doi.org/10.1126/scitranslmed.adx5758
Editor’s summary
The type I interferon (IFN-I) response is a conserved cascade of signaling and gene expression that, among other functions, confers protection of cells from viral infection. After resolution of infection, the response is tamped down by regulators such as IFN-I–stimulated gene 15 (ISG15). Cells from individuals lacking ISG15 are able to control viral infections in vitro as a consequence of maintaining a low-grade IFN-I response. Inspired by this observation, Akalu et al. identified a set of 10 ISGs that mimicked what is observed in cells from individuals lacking ISG15, with the idea that these 10 ISGs could serve as a broad-spectrum antiviral. The authors found that the 10 ISGs enabled control of multiple viral infections in vitro and lessened disease severity of SARS-CoV-2 when prophylactically administered as mRNAs to mice. Although limited delivery of the mRNAs may have restricted efficacy, as discussed by the authors, these data lay the foundation for development of a broad-spectrum antiviral prophylactic. —Courtney Malo
Abstract
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.
