title: IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses.
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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
authors.forename: Caroline
authors.initials: C
authors.lastname: Lai
authors.forename: Natalia
authors.initials: N
authors.lastname: Frias-Staheli
authors.forename: Nadia V
authors.initials: NV
authors.lastname: Giannakopoulos
authors.forename: Andrew
authors.initials: A
authors.lastname: Lutz
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.forename: Anna
authors.initials: A
authors.lastname: Osiak
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: David A
authors.initials: DA
authors.lastname: Leib
authors.forename: Andrew
authors.initials: A
authors.lastname: Pekosz
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.forename: Ivan
authors.initials: I
authors.lastname: Horak
authors.forename: Herbert Whiting
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D004198:Disease Susceptibility; D006564:Herpesviridae / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000502:physiology*; D012845:Sindbis Virus / Q000502:physiology*; D014452:Ubiquitins / Q000235:genetics / Q000502:physiology
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D014452:Ubiquitins