Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein.
We present a novel mechanism by which viruses may inhibit the alpha/beta interferon (IFN-alpha/beta) cascade. The double-stranded RNA (dsRNA) binding protein NS1 of influenza virus is shown to prevent the potent antiviral interferon response by inhibiting the activation of interferon regulatory factor 3 (IRF-3), a key regulator of IFN-alpha/beta gene expression. IRF-3 activation and, as a consequence, IFN-beta mRNA induction are inhibited in wild-type (PR8) influenza virus-infected cells but not in cells infected with an isogenic virus lacking the NS1 gene (delNS1 virus). Furthermore, NS1 is shown to be a general inhibitor of the interferon signaling pathway. Inhibition of IRF-3 activation can be achieved by the expression of wild-type NS1 in trans, not only in delNS1 virus-infected cells but also in cells infected with a heterologous RNA virus (Newcastle disease virus). We propose that inhibition of IRF-3 activation by a dsRNA binding protein significantly contributes to the virulence of influenza A viruses and possibly to that of other viruses.
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
J
J
Talon
C M
CM
Horvath
R
R
Polley
C F
CF
Basler
T
T
Muster
P
P
Palese
A
A
García-Sastre
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000378:metabolism; D009154:Mutation; D009522:Newcastle disease virus / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018108:Respirovirus / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C085820:INS1 protein, influenza virus; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D012333:RNA, Messenger; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta