Influenza A virus protein PB1-F2 exacerbates IFN-beta expression of human respiratory epithelial cells.
The PB1-F2 protein of the influenza A virus (IAV) contributes to viral pathogenesis by a mechanism that is not well understood. PB1-F2 was shown to modulate apoptosis and to be targeted by the CD8(+) T cell response. In this study, we examined the downstream effects of PB1-F2 protein during IAV infection by measuring expression of the cellular genes in response to infection with wild-type WSN/33 and PB1-F2 knockout viruses in human lung epithelial cells. Wild-type virus infection resulted in a significant induction of genes involved in innate immunity. Knocking out the PB1-F2 gene strongly decreased the magnitude of expression of cellular genes implicated in antiviral response and MHC class I Ag presentation, suggesting that PB1-F2 exacerbates innate immune response. Biological network analysis revealed the IFN pathway as a link between PB1-F2 and deregulated genes. Using quantitative RT-PCR and IFN-β gene reporter assay, we determined that PB1-F2 mediates an upregulation of IFN-β expression that is dependent on NF-κB but not on AP-1 and IFN regulatory factor-3 transcription factors. Recombinant viruses knocked out for the PB1-F2 and/or the nonstructural viral protein 1 (the viral antagonist of the IFN response) genes provide further evidence that PB1-F2 increases IFN-β expression and that nonstructural viral protein 1 strongly antagonizes the effect of PB1-F2 on the innate response. Finally, we compared the effect of PB1-F2 variants taken from several IAV strains on IFN-β expression and found that PB1-F2-mediated IFN-β induction is significantly influenced by its amino acid sequence, demonstrating its importance in the host cell response triggered by IAV infection.
Le Goffic
Ronan
R
Unité de Virologie et Immunologie Moléculaires, Unité de Recherche 892 Institut National de la Recherche Agronomique, Domaine de Vilvert, Jouy-en-Josas, France. ronan.legoffic@jouy.inra.fr
Bouguyon
Edwige
E
Chevalier
Christophe
C
Vidic
Jasmina
J
Da Costa
Bruno
B
Leymarie
Olivier
O
Bourdieu
Christiane
C
Decamps
Laure
L
Dhorne-Pollet
Sophie
S
Delmas
Bernard
B
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D007251:Influenza, Human / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D014774:Virulence / Q000235:genetics
C442816:PB1-F2 protein, Influenza A virus; D014764:Viral Proteins; D016899:Interferon-beta