Interferon-antagonistic activity of the Bunyavirus protein NSs.

Interferons (IFNs) are the first line of defense against viruses. Infected cells secrete IFN-alphy and -beta that stimulate synthesis of antiviral effector proteins, thereby limiting the spread of infection. The high effectiveness of the cellular IFN response forced viruses to evolve specific mechanisms to antagonize the induction or actions of IFNs. The family Bunyaviridae contains several members that cause encephalitis or hemorrhagic fevers in man e.g. Hantaan, Rift Valley fever, La Crosse and Crimean-Congo hemorrhagic fever viruses. They are posing an increasing threat to human health, examples of the so-called "Emerging Infections". Prototype of the Bunyaviridae is the Bunyamwera virus (BUN), which is also the only family member that can be rescued from cloned cDNA. Similar to other bunyaviruses, BUN contains a genome comprising three segments (L, M, and S) of negative-strand RNA. The smallest segment, S, encodes the structural protein N and the non-structural protein NSs in overlapping reading frames. Recent studies by our group provided evidence that NSs is a powerful virulence factor. A rescued virus that does not synthesise NSs, called BUNdelNSs, is attenuated in cell culture and in Balb/c mice. In particular, the abrogation of NSs expression changed BUN from a non-inducer to an inducer of IFNs. We found that NSs inhibits a signal transduction pathway which leads from double-stranded RNA, a by-product of viral replication, to the activation of the IFN transcription factors IRF-3 and NFkB. Our future studies will be focused on the mechanism how NSs inhibits IFN induction, and whether NSs is also controlling specific antiviral functions induced by IFN. Elucidation of the mechanism of IFN antagonists such as BUN NSs may lead to novel therapeutic and preventive strategies for the control of viral diseases.

Additional information: http://www.ukl.uni-freiburg.de/microbio
contact person: Dr. Friedemann Weber
Phone: (0761) 203-6614
Email: friedemann.weber@uniklinik-freiburg.de

Start of project: 01.11.2000
End of project: 31.10.2003

Albert-Ludwigs-University Freiburg
Weber Friedemann
Department für Medizinische Mikrobiologie und Hygiene
Institut für Virologie
Hermann-Herder-Strasse 11
79104 Freiburg
Germany

Phone: +49 761 203 6534
Fax: +49 761 203 6626
http://www.virologie.uniklinik-freiburg.de
Actual Research Report

NSs protein, reverse genetics, host cell shutoff, interferon antagonist

• Bridgen A., Weber F., Fazakerley J.K., Elliott R.M.: Bunyamwera bunyavirus nonstructural protein NSs is a nonessential gene product that contributes to viral pathogenesis. P Natl Acad Sci Usa, 2001; 98 (2): 664-669.