224: Resistance to respiratory syncytial virus replication is STAT1 and STAT2 dependent, but I interferon independent

Despite the known ability of type I IFNs to inhibit virus replication, we and others noted that mice lacking the IFN-αβ Receptor (IFNAR−/−) did not show increased sensitivity to either influenza A virus (IAV) or respiratory syncytial virus (RSV) infection. An explanation for this seemingly contradictory result was offered by the discovery of type III or IFN-λ, a unique family of cytokines that bind a distinct receptor but can also promote interferon stimulated gene factor 3 (ISGF3) formation and the transcriptional upregulation of IFN-stimulated genes. The presence of robust IFN-λ induction in IAV-infected IFNAR−/− mice can explain their resistance to infection, but a distinct protective mechanism is at work in RSV-infected IFNAR−/− animals. In the absence of the IFNAR, no type III IFN RNA or protein can be detected in RSV-infected animals, nor is there any evidence of ISGF3 formation or upregulation of the ISGF3 dependent gene, Mx1. Nonetheless, we observe enhanced virus susceptibility to RSV in mice lacking either STAT1 or STAT2. We therefore conclude from our studies that (1) triggering of IFN-λ synthesis is pathogen dependent: induction of IFN-λ by RSV, but not by IAV, is dependent on functional type I IFN signaling, and (2) resistance to RSV is mediated by a novel STAT1/STAT2 containing complex.