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* Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136; and
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032
The induction of type I (
) IFN following virus infection is necessary for the stimulation of effective antiviral host defense. In fibroblasts, a subset of primary genes (including those encoding IFN- and IFN-4) are induced directly by intracellular dsRNA generated by the virus during its replication. These primary type I IFNs induce expression of IFN regulatory factor (IRF)-7, required for production of a second cascade of IFN- subtypes and the further establishment of a complete antiviral state. Previously, we had reported on a role for Fas-associated death domain-containing protein (FADD) in the control of TLR-independent innate immune responses to virus infection. Our data in this study demonstrate that FADD is not only required for efficient primary gene induction, but is also essential for induction of Irf7 and effective expression of secondary IFN-s and other antiviral genes. Ectopic overexpression of IRF-7 partially rescued dsRNA responsiveness and IFN- production, and a constitutively active variant of IRF-7 displayed normal activity in Fadd–/– murine embryonic fibroblasts. MC159, a FADD-interacting viral protein encoded by the molluscum contagiosum poxvirus was found to inhibit dsRNA-activated signaling events upstream of IRF-7. These data indicate that FADD’s antiviral activity involves regulation of IRF-7-dependent production of IFN- subtypes and consequent induction of secondary antiviral genes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Defense Advanced Research Projects Agency and National Institutes of Health Grant R01GM068448 (to P.B.F.).
2 S.B. and T.V. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Glen N. Barber, Room 511, Papanicolaou Building, 1550 Northwest Tenth Avenue, University of Miami School of Medicine, Miami, FL 33136. E-mail address: gbarber{at}med.miami.edu
4 Abbreviations used in this paper: PKR, protein kinase R; FADD, Fas-associated death domain-containing protein; IMD, immune deficiency; RIG-I, retinoic acid-inducible gene I; MDA, melanoma differentiation Ag; CARD, caspase recruitment domain; TBK, tank binding kinase; IKK, I
B kinase; IPS, IFN- promoter stimulator; IRF, IFN regulatory factor; TRAF, TNFR-associated factor; MEF, murine embryonic fibroblast; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-; SA, superactive; IRAK, IL-1R-associated kinase; VSV, vesicular stomatitis virus; SeV, Sendai virus; m.o.i., multiplicity of infection; HA, hemagglutinin.
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