The host response to viral infection is complex and must balance inhibiting replication of the pathogen (disease resistance) with limiting damage to the host (disease tolerance). A key mediator of the host response to viral infection are type I interferons and the hundreds of interferon stimulated genes they induce. Among these, the ubiquitin-like protein ISG15, functions as an antiviral protein, limiting replication of many viruses. Our studies have demonstrated that ISG15 can also regulate the host response and recovery from viral infection, independent of any effects on viral replication, a process known as disease tolerance. During respiratory viral infection we have detected increased epithelial damage in both cells and mice lacking ISG15. In this proposal we will explore the mechanism by which ISG15 protects the epithelium from damage during acute viral infection. In Aim 1 we will determine if ISG15 protects the host by regulating the type of cell death, apoptosis vs. necroptosis, initiated in respiratory epithelial cells during acute viral infection. In Aim 2 we will determine if ISG15, through its interactions with RIPK1 and RIPK3, functions as a molecular switch to regulate the induction of necroptosis and apoptosis during influenza A virus infection. Understanding the mechanism by which ISG15 protects the host from viral infection, both through inhibition of viral replication and by limiting the damage induced to the host may lead to the development of therapies that target this pathway and can be used for the treatment of acute viral infections.