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Journal of Virology, August 2003, p. 8661-8668, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.8661-8668.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nonstructural Proteins NS1 and NS2 of Bovine Respiratory Syncytial Virus Block Activation of Interferon Regulatory Factor 3

Birgit Bossert, Sabrina Marozin, and Karl-Klaus Conzelmann*

Max von Pettenkofer Institute and Gene Center, Ludwig Maximilians University Munich, D-81377 Munich, Germany

Received 26 February 2003/ Accepted 29 May 2003

We have previously shown that the nonstructural (NS) proteins NS1 and NS2 of bovine respiratory syncytial virus (BRSV) mediate resistance to the alpha/beta interferon (IFN)-mediated antiviral response. Here, we show that they, in addition, are able to prevent the induction of beta IFN (IFN-ß) after virus infection or double-stranded RNA stimulation. In BRSV-infected MDBK cells upregulation of IFN-stimulated genes (ISGs) such as MxA did not occur, although IFN signaling via JAK/STAT was found intact. In contrast, infection with recombinant BRSVs lacking either or both NS genes resulted in efficient upregulation of ISGs. Biological IFN activity and IFN-ß were detected only in supernatants of cells infected with the NS deletion mutants but not with wild-type (wt) BRSV. Subsequent analyses of IFN-ß promoter activity showed that infection of cells with the double deletion mutant BRSV {Delta}NS1/2, but not with BRSV wt, resulted in a significant increase in IFN-ß gene promoter activity. Induction of the IFN-ß promoter depends on the activation of three distinct transcription factors, NF-{kappa}B, ATF-2/c-Jun, and IFN regulatory factor 3 (IRF-3). Whereas NF-{kappa}B and ATF-2/c-Jun activities were readily detectable and comparable in both wt BRSV- and BRSV {Delta}NS1/2-infected cells, phosphorylation and transcriptional activity of IRF-3, however, were observed only after BRSV {Delta}NS1/2 infection. NS protein-mediated inhibition of IRF-3 activation and IFN induction should have considerable impact on the pathogenesis and immunogenicity of BRSV.

* Corresponding author. Mailing address: Max von Pettenkofer Institute and Gene Center, Feodor-Lynen-Str. 25, D-81377 Munich, Germany. Phone: 49 89 2180 6851. Fax: 49 89 2180 6899. E-mail: conzelma{at}lmb.uni-muenchen.de.

Journal of Virology, August 2003, p. 8661-8668, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.8661-8668.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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