Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia

The response of cells to virus infection depends on Interferons (IFNs), a group of cytokines which activate the expression of hundreds of genes that help control viral replication inside infected cells. While type I IFN was discovered in 1957, type III IFN (IFNλ, IL-28/29) was characterized recently and is known for its role in the response to hepatitis C virus. Airway epithelia are the primary target of influenza virus, and we studied how infection induces IFNs and which IFN is most important for the epithelial anti-influenza response. We found that infected epithelia detect virus through the cytoplasmic RIG-I/MAVS recognition system, leading to activation of the transcription factor IRF7 and subsequent induction of both type I and III IFNs. All ensuing cellular responses to infection are dependent on the production and secretion of IFNs, as responses are lost in epithelia lacking receptors for both type I and III IFNs. Finally, gene induction is indistinguishable in single receptor-deficient and wild-type cells, indicating that the two IFN systems are completely redundant in epithelia. Thus, influenza infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two overlapping and redundant amplification loops to upregulate antiviral genes.