Bunyamwera bunyavirus nonstructural protein NSs counteracts the induction of alpha/beta interferon.
Production of alpha/beta interferons (IFN-alpha/beta) in response to viral infection is one of the main defense mechanisms of the innate immune system. Many viruses therefore encode factors that subvert the IFN system to enhance their virulence. Bunyamwera virus (BUN) is the prototype of the Bunyaviridae family. By using reverse genetics, we previously produced a recombinant virus lacking the nonstructural protein NSs (BUNdelNSs) and showed that NSs is a nonessential gene product that contributes to viral pathogenesis. Here we demonstrate that BUNdelNSs is a strong inducer of IFN-alpha/beta, whereas in cells infected with the wild-type counterpart expressing NSs (wild-type BUN), neither IFN nor IFN mRNA could be detected. IFN induction by BUNdelNSs correlated with activation of NF-kappaB and was dependent on virally produced double-stranded RNA and on the IFN transcription factor IRF-3. Furthermore, both in cultured cells and in mice lacking a functional IFN-alpha/beta system, BUNdelNSs replicated to wild-type BUN levels, whereas in IFN-competent systems, wild-type BUN grew more efficiently. These results suggest that BUN NSs is an IFN induction antagonist that blocks the transcriptional activation of IFN-alpha/beta in order to increase the virulence of Bunyamwera virus.
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Germany.
Friedemann
F
Weber
Anne
A
Bridgen
John K
JK
Fazakerley
Hein
H
Streitenfeld
Nina
N
Kessler
Richard E
RE
Randall
Richard M
RM
Elliott
D000818:Animals; D002042:Bunyamwera virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D002044:Bunyaviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005814:Genes, Viral; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*; D014774:Virulence; D014779:Virus Replication
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; C494233:Irf3 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; C423923:NSs protein, Bunyamwera bunyavirus; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D017471:Receptors, Interferon; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta