title: Alleles A and B of non-structural protein 1 of avian influenza A viruses differentially inhibit beta interferon production in human and mink lung cells.
abstract: Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-α/β) for the efficient replication and pathogenicity of influenza A viruses. Here, we reveal another dimension of the NS1 protein of avian influenza A viruses in suppressing IFN-β production in cultured cell lines. We found that allele A NS1 proteins of H6N8 and H4N6 have a strong capacity to inhibit the activation of IFN-β production, compared with allele B from corresponding subtypes, as measured by IFN stimulatory response element (ISRE) promoter activation, IFN-β mRNA transcription and IFN-β protein expression. Furthermore, the ability to suppress IFN-β promoter activation was mapped to the C-terminal effector domain (ED), while the RNA-binding domain (RBD) alone was unable to suppress IFN-β promoter activation. Chimeric studies indicated that when the RBD of allele A was fused to the ED of allele B, it was a strong inhibitor of IFN-β promoter activity. This shows that well-matched ED and RBD are crucial for the function of the NS1 protein and that the RBD could be one possible cause for this differential IFN-β inhibition. Notably, mutagenesis studies indicated that the F103Y and Y103F substitutions in alleles A and B, respectively, do not influence the ISRE promoter activation. Apart from dsRNA signalling, differences were observed in the expression pattern of NS1 in transfected human and mink lung cells. This study therefore expands the versatile nature of the NS1 protein in inhibiting IFN responses at multiple levels, by demonstrating for the first time that it occurs in a manner dependent on allele type.
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Division of Virology, and Joint Research and Development, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA) and Swedish University of Agricultural Sciences (SLU), Ulls väg 2B, SE-751 89 Uppsala, Sweden.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Munir
authors.affiliation: R&D Unit for Virology, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA), Ulls väg 2B, SE-751 89 Uppsala, Sweden.|Department of Biomedical Sciences and Veterinary Public Health, Division of Virology, and Joint Research and Development, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA) and Swedish University of Agricultural Sciences (SLU), Ulls väg 2B, SE-751 89 Uppsala, Sweden.
authors.forename: Siamak
authors.initials: S
authors.lastname: Zohari
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Division of Virology, and Joint Research and Development, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA) and Swedish University of Agricultural Sciences (SLU), Ulls väg 2B, SE-751 89 Uppsala, Sweden.
authors.forename: Giorgi
authors.initials: G
authors.lastname: Metreveli
authors.affiliation: R&D Unit for Virology, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA), Ulls väg 2B, SE-751 89 Uppsala, Sweden.
authors.forename: Claudia
authors.initials: C
authors.lastname: Baule
authors.affiliation: R&D Unit for Virology, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA), Ulls väg 2B, SE-751 89 Uppsala, Sweden.|Department of Biomedical Sciences and Veterinary Public Health, Division of Virology, and Joint Research and Development, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA) and Swedish University of Agricultural Sciences (SLU), Ulls väg 2B, SE-751 89 Uppsala, Sweden.
authors.forename: Sándor
authors.initials: S
authors.lastname: Belák
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Division of Virology, and Joint Research and Development, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA) and Swedish University of Agricultural Sciences (SLU), Ulls väg 2B, SE-751 89 Uppsala, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Berg
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000821:virology; D008907:Mink; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C085820:INS1 protein, influenza virus; D050505:Mutant Proteins; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D016899:Interferon-beta