Influenza A virus NS1 protein prevents activation of NF-kappa B and induction of alpha/beta interferon

The alpha/beta interferon (IFN-alpha/beta) system represents one of the fir st lines of defense against virus infections. As a result, most viruses enc ode IFN antagonistic factors which enhance viral replication in their hosts . We have previously shown that a recombinant influenza A virus lacking the NS1 gene (delNS1) only replicates efficiently in IFN-alpha/beta -deficient systems. Consistent with this observation, we found that infection of tiss ue culture cells with delNS1 virus, but not with wild-type influenza A viru s, induced high levels of mRNA synthesis from IFN-alpha/beta genes, includi ng IFN-beta. It is known that transactivation of the IFN-beta promoter depe nds on NF-kappaB and several other transcription factors. Interestingly, ce lls infected with delNS1 virus showed high levels of NF-kappaB activation c ompared with those infected with wild-type virus. Expression of dominant-ne gative inhibitors of the NF-kappaB pathway during deINS1 virus infection pr evented the transactivation of the IFN-beta promoter, demonstrating a funct ional link between NF-kappaB activation and IFN-alpha/beta synthesis in deI NS1 virus-infected cells. Moreover, expression of the NS1 protein prevented virus- and/or double-stranded RNA (dsRNA)-mediated activation of the NF-ka ppaB pathway and of IFN-beta synthesis. This inhibitory property of the NS1 protein of influenza A virus was dependent on its ability to bind dsRNA, s upporting a model in which binding of NS1 to dsRNA generated during influen za virus infection prevents the activation of the IFN system. NS1-mediated inhibition of the NF-kappaB pathway may thus play a key role in the pathoge nesis of influenza A virus.