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

doi:10.1073/pnas.0607038104

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

Departments of *Pathology and Immunology,
^§Molecular Microbiology, and
^††Ophthalmology, Washington University School of Medicine, St. Louis, MO 63110;
^†Department of Microbiology and
^‡Microbiology Graduate School Training Program, Mount Sinai School of Medicine, New York, NY 10029;
^¶P15, Robert Koch-Institute, 13353 Berlin, Germany;
^‖Abteilung Molekulare Leibniz Institute für Molekulare Pharmakologie, 13125 Berlin, Germany; and
**Departments of Internal Medicine and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390

Edited by Francis V. Chisari, The Scripps Research Institute, La Jolla, CA, and approved November 22, 2006 (received for review August 14, 2006)

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.

Footnotes

^‡‡To whom correspondence should be addressed at:
Washington University School of Medicine, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110.
E-mail: virgin{at}wustl.edu
Author contributions: D.J.L., B.L., A.P., and H.W.V. designed research; D.J.L., C.L., N.F.-S., N.V.G., A.L., and D.A.L. performed research; T.W., A.O., A.G.-S., K.-P.K., and I.H. contributed new reagents/analytic tools; D.J.L., B.L., R.E.S., A.G.-S., D.A.L., A.P., and H.W.V. analyzed data; and D.J.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0607038104/DC1.
Abbreviations:

γHV68,

gammaherpesvirus 68;

HIV-1,

human immunodeficiency virus type 1;

HSV,

herpes simplex virus 1;

i.c.,

intracranial/intracranially;

IFNαβR,

IFN-αβ receptor;

i.n.,

intranasal/intranasally;

ISG,

interferon-stimulated gene;

LCMV,

lymphocytic choriomeningitis virus;

MDCK,

Madin–Darby canine kidney;

MEF,

murine embryonic fibroblast;

VSV,

vesicular stomatitis virus.