Virus versus host: modulation of the host α/β interferon pathways by the influenza A virus NS1 protein

Abstract

α/β Interferons (IFN) represent one of the first host responses against viral infection. IFN activates a signaling cascade involving multiple genes and pathways leading to the stop of viral replication. However, many viruses have developed mechanisms to overcome this first line of the host defense. We studied the IFN antagonist properties of the NS1 protein of influenza A virus. The NS1 protein is a dsRNA binding protein. Since dsRNAs produced during viral infection are potent activators of the IFN cascade, sequestering of dsRNA by the NS1 protein might prevent the IFN response during influenza virus infection. To test in vivo the anti-IFN activity of NS1, we investigated the biological properties of a recombinant influenza virus lacking the NS1 gene (delNS1). delNS1 virus replication is highly compromised in IFN competent hosts. However, this mutant virus replicates efficiently in IFN deficient hosts. Moreover, infection with delNS1 virus stimulates IFN production by activating NF-κB and IFN regulatory factor 3 (IRF-3) transcription factors. DelNS1 virus reacquires virulence and replicates in lungs of PKR −/− mice, also suggesting an important role of NS1 in the inhibition of PKR, an important component of the IFN system. These data underline the importance of NS1-mediated inhibition of IFN activated pathways in the pathogenesis of influenza A virus infection.