Human influenza viruses activate an interferon-independent transcription of cellular antiviral genes: Outcome with influenza A virus is unique

Abstract

We examine the IFN-␣͞␤-independent activation of cellular transcription that constitutes an early antiviral response of cells against influenza A and B viruses, which cause widespread epidemics in humans. We show that influenza B virus induces the synthesis in human cells of several mature mRNAs encoded by genes containing an IFN-␣͞␤-stimulated response element (ISRE). Consequently, the IFN regulatory factor-3 transcription factor, which is required for the transcription of ISRE-controlled genes, is activated after influenza B virus infection. The production of these cellular mRNAs, some of which encode antiviral proteins, is independent of not only IFN-␣͞␤, but also viral protein synthesis. These mature cellular antiviral mRNAs are not produced after infection with influenza A virus, but IFN regulatory factor-3 is activated and the transcription of the ISRE-controlled p56 gene is induced. Consequently, like other newly synthesized cellular premRNAs in influenza A virusinfected cells, the posttranscriptional processing of premRNAs encoded by ISRE-controlled genes is inhibited. Previous work has established that such posttranscriptional inhibition is mediated by the viral NS1A protein. This unique, global countermeasure against the early, IFN-␣͞␤-independent antiviral response of cells may be an important factor in the pathogenicity of influenza A virus infection.

Structural basis for suppression of a host antiviral response by influenza A virus

“…After infection of cells for 7 h with the Ud virus, ϳ50% of the endogenous IRF-3 migrates in the position of the activated dimer (Fig. 5, lane 2), confirming our previous study (6). This activated dimeric IRF-3 functions to activate high level transcription of the IFN-␤ gene, as documented here by the accumulation of a substantial amount of unprocessed IFN-␤ pre-mRNA in infected cells (see Fig.…”

“…2D). A substantial amount of unprocessed IFN-␤ pre-mRNA was detected in WT virus-infected cells, verifying that the Ud virus activates transcription of the IFN-␤ gene via the activation of interferon regulatory factor (IRF)-3 and other transcription factors (6,9,26). Approximately 20% as much IFN-␤ pre-mRNA accumulated in G184R-infected cells, whereas the amount of mature IFN-␤ mRNA was approximately five times more than that in WT-infected cells.…”

“…However, it was not established that the effect of such accumulated NS1A protein on subsequent Sendai virus-induced IRF-3 activation accurately mirrors the actions of the NS1A protein on IRF-3 activation induced by influenza A virus itself at earlier times of infection. To address this issue, we directly assayed IRF-3 activation in influenza A virus-infected cells by measuring the formation of the homodimer of IRF-3 that results from the phosphorylation-dependent activation of IRF-3 (6,29). After infection of cells for 7 h with the Ud virus, ϳ50% of the endogenous IRF-3 migrates in the position of the activated dimer (Fig.…”

Heterologous interactions between NS1 proteins from different influenza A virus subtypes/strains

“…In our previous study, we also noticed a distinct distribution pattern of NS32 in Hela cells with NS11, NS51 and NS92 [27]. The unique nucleolus localization of NS32 protein may modulate the synthesis of host rRNA and hence affect the pathogenicity of the influenza virus [26,28]. Furthermore, we found that the NS32 protein exhibited remarkable variation in the transcription-stimulating capability in yeast when compared to NS11, NS51 and NS92 [29].…”

Frequency and Effects of Bacterial Infection in Children with Influenza Under Oseltamivir Treatment

“…These differences may result from the prevalent bacteria strains and different immune responses to influenza A and influenza B viruses 15 .…”