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Journal of Virology, July 2003, p. 7999-8008, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.7999-8008.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Bunyamwera Virus Nonstructural Protein NSs Counteracts Interferon Regulatory Factor 3-Mediated Induction of Early Cell Death

Alain Kohl,1 Reginald F. Clayton,2 Friedemann Weber,1,{dagger} Anne Bridgen,1,{ddagger} Richard E. Randall,3 and Richard M. Elliott1*

Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow,1 Medical Research Council Virology Unit, Glasgow G11 5JR,2 School of Biology, University of St. Andrews, St. Andrews KY16 9TS, Scotland, United Kingdom3

Received 14 January 2003/ Accepted 21 April 2003

The genome of Bunyamwera virus (BUN; family Bunyaviridae, genus Orthobunyavirus) consists of three segments of negative-sense RNA. The smallest segment, S, encodes two proteins, the nonstructural protein NSs, which is nonessential for viral replication and transcription, and the nucleocapsid protein N. Although a precise role in the replication cycle has yet to be attributed to NSs, it has been shown that NSs inhibits the induction of alpha/beta interferon, suggesting that it plays a part in counteracting the host antiviral defense. A defense mechanism to limit viral spread is programmed cell death by apoptosis. Here we show that a recombinant BUN that does not express NSs (BUNdelNSs) induces apoptotic cell death more rapidly than wild-type virus. Screening for apoptosis pathways revealed that the proapoptotic transcription factor interferon regulatory factor 3 (IRF-3) was activated by both wild-type BUN and BUNdelNSs infection, but only wild-type BUN was able to suppress signaling downstream of IRF-3. Studies with a BUN minireplicon system showed that active replication induced an IRF-3-dependent promoter, which was suppressed by the NSs protein. In a cell line (P2.1) defective in double-stranded RNA signaling due to low levels of IRF-3, induction of apoptosis was similar for wild-type BUN and BUNdelNSs. These data suggest that the BUN NSs protein can delay cell death in the early stages of BUN infection by inhibiting IRF-3-mediated apoptosis.

* Corresponding author. Mailing address: Institute of Virology, University of Glasgow, Church St., Glasgow G11 5JR, Scotland, United Kingdom. Phone: 44 141 330 4024. Fax: 44 141 337 2236. E-mail: r.elliott{at}vir.gla.ac.uk.

{dagger} Present address: Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79104 Freiburg, Germany.

{ddagger} Present address: Department of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, United Kingdom.

Journal of Virology, July 2003, p. 7999-8008, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.7999-8008.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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