Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo.
The innate immune response, and in particular the alpha/beta interferon (IFN-alpha/beta) system, plays a critical role in the control of viral infections. Interferons alpha and beta exert their antiviral effects through the induction of hundreds of interferon-induced (or -stimulated) genes (ISGs). While several of these ISGs have characterized antiviral functions, their actions alone do not explain all of the effects mediated by IFN-alpha/beta. To identify additional IFN-induced antiviral molecules, we utilized a recombinant chimeric Sindbis virus to express selected ISGs in IFN-alpha/beta receptor (IFN-alpha/betaR)(-/-) mice and looked for attenuation of Sindbis virus infection. Using this approach, we identified a ubiquitin homolog, interferon-stimulated gene 15 (ISG15), as having antiviral activity. ISG15 expression protected against Sindbis virus-induced lethality and decreased Sindbis virus replication in multiple organs without inhibiting the spread of virus throughout the host. We establish that, much like ubiquitin, ISG15 requires its C-terminal LRLRGG motif to form intracellular conjugates. Finally, we demonstrate that ISG15's LRLRGG motif is also required for its antiviral activity. We conclude that ISG15 can be directly antiviral.
Lenschow
Deborah J
DJ
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Giannakopoulos
Nadia V
NV
Gunn
Lacey J
LJ
Johnston
Christine
C
O'Guin
Andy K
AK
Schmidt
Robert E
RE
Levine
Beth
B
Virgin
Herbert W
HW
D018354:Alphavirus Infections / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016898:Interferon-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016899:Interferon-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D012845:Sindbis Virus / Q000235:genetics* / Q000472:pathogenicity; D014162:Transfection; D014452:Ubiquitins / Q000235:genetics / Q000502:physiology
D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D016898:Interferon-alpha; D014452:Ubiquitins; D016899:Interferon-beta