Innate Immune Mechanisms of Controlling Respiratory Virus Infection

Interferons (IFN) are a family of cytokines that are well known for their ability to inhibit virus replication. IFNs are classified as type I (IFN-α/β), type II (IFN-γ), or type III (IFN-λ) according to sequence homology and receptor binding. The type III IFNs are the most recently discovered and, despite evidence of their antiviral effects in vitro, little is known about their relative importance to antiviral immunity in vivo. It has been believed that IFN-α/β represent the most critical component of innate antiviral immune responses based on reports demonstrating heightened sensitivity to viral infection in mouse models lacking the type I IFN receptor (IFNαβR-/-). However, we and others have demonstrated that IFNαβR-/- mice are, in fact, not more susceptible to infection with either respiratory syncytial virus (RSV) or a pneumotropic strain of influenza A virus while STAT1-/- mice, which lack signaling from all three IFN receptors, are more susceptible. The experiments detailed here test the hypothesis that IFN-λ is capable of fully compensating for the loss of IFN-α/β signaling in protecting the murine host against respiratory virus infection. In support of this hypothesis we observed that IFN-λ is the major IFN induced following influenza virus infection, with peak levels exceeding that of IFN-α and IFN-β by ~10-fold in both wild-type and IFN-αβR-/- mice. Importantly, the levels of IFN-λ induced in vivo are more than sufficient to protect respiratory epithelium from virus challenge as demonstrated in an in vitro antiviral assay. Also, mice lacking both type I and type III IFN signaling are highly sensitive to fatal influenza virus infection, a result which supports an important role for IFN-λ in antiviral protection. Surprisingly, we could not detect expression of IFN-λ during RSV infection of IFNαβR-/- mice suggesting that protection, in this case, is coming from a novel signaling pathway. Moreover, protection against RSV infection in the absence of the IFNαβR occurred without activation of ISGF3, the transcription factor that is responsible for the induction of many of the antiviral interferon stimulated genes.