Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon.
The alpha/beta interferon (IFN-alpha/beta) system represents one of the first lines of defense against virus infections. As a result, most viruses encode 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 tissue culture cells with delNS1 virus, but not with wild-type influenza A virus, induced high levels of mRNA synthesis from IFN-alpha/beta genes, including IFN-beta. It is known that transactivation of the IFN-beta promoter depends on NF-kappaB and several other transcription factors. Interestingly, cells infected with delNS1 virus showed high levels of NF-kappaB activation compared with those infected with wild-type virus. Expression of dominant-negative inhibitors of the NF-kappaB pathway during delNS1 virus infection prevented the transactivation of the IFN-beta promoter, demonstrating a functional link between NF-kappaB activation and IFN-alpha/beta synthesis in delNS1 virus-infected cells. Moreover, expression of the NS1 protein prevented virus- and/or double-stranded RNA (dsRNA)-mediated activation of the NF-kappaB 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, supporting a model in which binding of NS1 to dsRNA generated during influenza 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 pathogenesis of influenza A virus.
Wang
X
X
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Li
M
M
Zheng
H
H
Muster
T
T
Palese
P
P
Beg
A A
AA
García-Sastre
A
A
D000818:Animals; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D009980:Influenza A virus; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
C085820:INS1 protein, influenza virus; D016898:Interferon-alpha; D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta