IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses

Deborah J. Lenschow, Caroline Lai, Natalia Frias-Staheli, Nadia V. Giannakopoulos, Andrew Lutz, Thorsten Wolff, Anna Osiak, Beth Levine, Robert E. Schmidt, Adolfo García-Sastre, David A. Leib, Andrew Pekosz, Klaus Peter Knobeloch, Ivan Horak, Herbert Whiting Virgin IV

Research output: Contribution to journalArticle

351 Scopus citations

Abstract

Type I interferons (IFNs) play an essential role in the host response to viral infection through the induction of numerous IFN-stimulated genes (ISGs), including important antiviral molecules such as PKR, RNase L, Mx, and iNOS. Yet, additional antiviral ISGs likely exist. IFN-stimulated gene 15 (ISG15) is a ubiquitin homolog that is rapidly up-regulated after viral infection, and it conjugates to a wide array of host proteins. Although it has been hypothesized that ISG15 functions as an antiviral molecule, the initial evaluation of ISG15-deficient mice revealed no defects in their responses to vesicular stomatitis virus or lymphocytic choriomeningitis virus, leaving open the important question of whether ISG15 is an antiviral molecule in vivo. Here we demonstrate that ISG15 is critical for the host response to viral infection. ISG15-/- mice are more susceptible to influenza A/WSN/33 and influenza B/Lee/40 virus infections. ISG15-/- mice also exhibited increased susceptibility to both herpes simplex virus type 1 and murine gammaherpesvirus 68 infection and to Sindbis virus infection. The increased susceptibility of ISG15-/- mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome. The demonstration of ISG15 as a novel antiviral molecule with activity against both RNA and DNA viruses provides a target for the development of therapies against important human pathogens.

Original languageEnglish
Pages (from-to)1371-1376
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number4
DOIs
StatePublished - Jan 23 2007

Keywords

  • DNA viruses
  • Innate immunity
  • RNA viruses
  • Ubiquitin
  • Viral pathogenesis

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    Lenschow, D. J., Lai, C., Frias-Staheli, N., Giannakopoulos, N. V., Lutz, A., Wolff, T., Osiak, A., Levine, B., Schmidt, R. E., García-Sastre, A., Leib, D. A., Pekosz, A., Knobeloch, K. P., Horak, I., & Virgin IV, H. W. (2007). IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proceedings of the National Academy of Sciences of the United States of America, 104(4), 1371-1376. https://doi.org/10.1073/pnas.0607038104