IFN-κ protects against influenza A
Virus-infected cells produce type I interferons (IFNs), which protect neighboring cells from infection by stimulating innate defenses. He et al. found that IFN-κ was produced in the lungs of mice early after infection with various influenza A viruses (IAVs). In cultured human lung epithelial cells, IFN-κ inhibited IAV replication by stimulating the IFN receptors IFNAR1 and IFNAR2, and chromodomain helicase DNA binding protein 6 (CHD6) was a key effector of IFN-κ antiviral activity. IFN-κ–mediated induction of CHD6 expression required the kinase p38 MAPK and the transcription factor c-Fos. Pretreating mice with IFN-κ protected them from subsequent lethal influenza challenge, suggesting that IFN-κ therapy may be useful for preventing or treating IAV infection in humans.
Abstract
Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-κ efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-κ, but not for that of IFN-α or IFN-β. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-κ protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-κ–specific pathway that constrains influenza A virus and provide evidence that IFN-κ may have potential as a preventative and therapeutic agent against influenza A virus.
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