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Journal of Virology, February 2000, p. 1513-1523, Vol. 74, No. 3
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Alpha/Beta Interferons Potentiate Virus-Induced Apoptosis through Activation of the FADD/Caspase-8 Death Signaling Pathway

Siddharth Balachandran,1,2,3 P. Christopher Roberts,3,dagger Todd Kipperman,3 Kapil N. Bhalla,2 Richard W. Compans,3 David R. Archer,4 and Glen N. Barber1,2,*

Department of Microbiology and Immunology1 and Sylvester Comprehensive Cancer Center,2 University of Miami School of Medicine, Miami, Florida 33136, and Department of Microbiology and Immunology3 and Department of Pediatrics,4 Emory University School of Medicine, Atlanta, Georgia 30322

Received 24 August 1999/Accepted 1 November 1999

Interferon (IFN) mediates its antiviral effects by inducing a number of responsive genes, including the double-stranded RNA (dsRNA)-dependent protein kinase, PKR. Here we report that inducible overexpression of functional PKR in murine fibroblasts sensitized cells to apoptosis induced by influenza virus, while in contrast, cells expressing a dominant-negative variant of PKR were completely resistant. We determined that the mechanism of influenza virus-induced apoptosis involved death signaling through FADD/caspase-8 activation, while other viruses such as vesicular stomatitis virus (VSV) and Sindbis virus (SNV) did not significantly provoke PKR-mediated apoptosis but did induce cytolysis of fibroblasts via activation of caspase-9. Significantly, treatment with IFN-alpha /beta greatly sensitized the fibroblasts to FADD-dependent apoptosis in response to dsRNA treatment or influenza virus infection but completely protected the cells against VSV and SNV replication in the absence of any cellular destruction. The mechanism by which IFN increases the cells' susceptibility to lysis by dsRNA or certain virus infection is by priming cells to FADD-dependent apoptosis, possibly by regulating the activity of the death-induced signaling complex (DISC). Conversely, IFN is also able to prevent the replication of viruses such as VSV that avoid triggering FADD-mediated DISC activity, by noncytopathic mechanisms, thus preventing destruction of the cell.

* Corresponding author. Mailing address: Rm. 511 Papanicolaou Building [M710], 1550 NW 10th Ave., University of Miami School of Medicine, Miami, FL 33136. Phone: (305) 243-5914. Fax: (305) 243-5885. E-mail: gbarber{at}med.miami.edu.

dagger Present address: Department of Microbiology and Immunology, Wayne State University, Detroit, Mich.

Journal of Virology, February 2000, p. 1513-1523, Vol. 74, No. 3
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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