Pleiotropic Roles of Type 1 Interferons in Antiviral Immune Responses

Since Isaac's and Lindenmann's seminal experiments over 50 years ago demonstrating a soluble factor generated from heat killed virus-stimulated chicken embryos could inhibit live influenza virus replication, the term interferon has been synonymous with inhibition of virus replication. While the antiviral properties of type 1 interferon (IFN-I) are undeniable, recent studies have reported expanding and somewhat unexpected roles of IFN-I signaling during both acute and persistent viral infections. IFN-I signaling can promote morbidity and mortality through induction of aberrant inflammatory responses and recruitment of inflammatory innate immune cell populations during acute respiratory viral infections. During persistent viral infection, IFN-I signaling promotes containment of early viral replication/dissemination, however, also initiates and maintains immune suppression, lymphoid tissue disorganization, and CD4 T cell dysfunction through modulation of multiple immune cell populations. Finally, new data are emerging illuminating how specific IFN-I species regulate immune pathology and suppression during acute and persistent viral infections, respectively. Systematic characterization of the cellular populations that produce IFN-I, how the timing of IFN-I induction and intricacies of subtype specific IFN-I signaling promote pathology or immune suppression during acute and persistent viral infections should inform the development of treatments and modalities to control viral associated pathologies.