Influenza is a leading cause of death in the US with a staggering economic burden. Interferons serve as a critical response to this virus triggering elaboration of host defense molecules within alveolar macrophages. A relatively new and unchartered area in interferon biology involves interferon lamda (IFN) acting through its cognate receptor, IFNLR1, to mediate anti-viral defense. Loss of IFNLR1 leads to viral dissemination and death in experimental influenza. The mechanistic platform of this proposal resides on our discovery of a unique molecular model whereby a protein, Fbxo45, rapidly impairs host defense by mediating ubiquitin-driven disposal of this crucial cytoprotective, anti-viral receptor, IFNLR1. Hence, in this application we will first elucidate how short-term influenza infection depletes IFNLR1 through Fbxo45, thereby accentuating experimental viral lung injury (Aim 1). We will specifically elucidate how Fbxo45 targets IFNLR1 for its degradation using complementary in vitro and in vivo genetic models. Next, after sustained influenza infection we observed that IFNLR1 mRNA levels increase in macrophages, perhaps as a compensatory host defense mechanism. Here we will assess novel post-transcriptional mechanisms mediated by microRNA acting on the 3’UTR of the IFNLR1 gene (Aim 2). These studies will provide a new pathobiologic model of lung injury that will serve as a platform for unveiling new molecular insight into the IFN- IFNLR1 axis that is indispensable to resolve inflammatory injury in subjects with severe virally-driven critical illness.