IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses.
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.
Lenschow
Deborah J
DJ
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Lai
Caroline
C
Frias-Staheli
Natalia
N
Giannakopoulos
Nadia V
NV
Lutz
Andrew
A
Wolff
Thorsten
T
Osiak
Anna
A
Levine
Beth
B
Schmidt
Robert E
RE
García-Sastre
Adolfo
A
Leib
David A
DA
Pekosz
Andrew
A
Knobeloch
Klaus-Peter
KP
Horak
Ivan
I
Virgin
Herbert Whiting
HW
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
D016207:Cytokines; C489550:G1p2 protein, mouse; D014452:Ubiquitins