Interferon induction and/or production and its suppression by influenza A viruses.
Developmentally aged chicken embryo cells which hyperproduce interferon (IFN) when induced were used to quantify IFN production and its suppression by eight strains of type A influenza viruses (AIV). Over 90% of the IFN-inducing or IFN induction-suppressing activity of AIV populations resided in noninfectious particles. The IFN-inducer moiety of AIV appears to preexist in, or be generated by, virions termed IFN-inducing particles (IFP) and was detectable under conditions in which a single molecule of double-stranded RNA introduced into a cell via endocytosis induced IFN, whereas single-stranded RNA did not. Some AIV strains suppressed IFN production, an activity that resided in a noninfectious virion termed an IFN induction-suppressing particle (ISP). The ISP phenotype was dominant over the IFP phenotype. Strains of AIV varied 100-fold in their capacity to induce IFN. AIV genetically compromised in NS1 expression induced about 20 times more IFN than NS1-competent parental strains. UV irradiation further enhanced the IFN-inducing capacity of AIV up to 100-fold, converting ISP into IFP and IFP into more efficient IFP. AIV is known to prevent IFN induction and/or production by expressing NS1 from a small UV target (gene NS). Evidence is presented for an additional downregulator of IFN production, identified as a large UV target postulated to consist of AIV polymerase genes PB1 + PB2 + PA, through the ensuing action of their cap-snatching endonuclease on pre-IFN-mRNA. The products of both the small and large UV targets act in concert to regulate IFN induction and/or production. Knowledge of the IFP/ISP phenotype may be useful in the development of attenuated AIV strains that maximally induce cytokines favorable to the immune response.
Marcus
Philip I
PI
Department of Molecular and Cell Biology, 91 North Eagleville Rd., U-3125, University of Connecticut, Storrs, CT 06269, USA. pmarcus@uconn.edu
Rojek
Jillian M
JM
Sekellick
Margaret J
MJ
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004307:Dose-Response Relationship, Radiation; D016679:Genome, Viral; D006358:Hot Temperature; D007108:Immune Tolerance; D009980:Influenza A virus / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000528:radiation effects; D007372:Interferons / Q000096:biosynthesis*; D007700:Kinetics; D012097:Repressor Proteins / Q000378:metabolism; D013045:Species Specificity; D014466:Ultraviolet Rays
D012097:Repressor Proteins; D007372:Interferons