Identification of novel type III IFN regulatory pathways

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ABSTRACT Interferons (IFN) straddle the balance between protective responses that maintain cellular integrity and the induction of deleterious inflammatory responses that cause irreversible tissue damage. The detection of viral infection or the accumulation of cellular stress triggers the synthesis of both type I (IFN/) and type III IFNs (IFNλ), which activate an overlapping JAK/STAT pathway to induce the expression of effector genes known as interferon stimulated genes (ISGs). While almost all nucleated cells can respond to IFN/ stimulation, the expression of the IFN receptor (IFNLR1) is restricted to a few cell types, primarily the epithelium. Studies on the evolutionary requirement for overlapping IFN functions, revealed context-specific functions for IFNs: IFN/ drive antiviral and proinflammatory responses that can promote tissue damage when unabated, and IFNλ confers antiviral protection with minimal inflammatory induction and reinforces the integrity of the barrier. My previous work has defined how divergent activation of canonical transcription factors (TF), interferon regulatory factors (IRF) and Signal transducer and activator of transcription (STAT), specifies maladaptive IFN/ functions. IFNλ responses also become maladaptive and hinder barrier repair, yet understanding of how parallel signaling events and cell identity disrupt the balance of the IFNλ pathophysiological functions is lacking. My future work will utilize a multidisciplinary approach to fill this knowledge gap. We will 1) determine how non-canonical signal integration, such as NF-kB and MAPK, defines the IFNλ-dependent barrier functions, 2) define how cell identity controls cytokine sensitivity, and 3) leverage genetics to identify novel cell-type specific, non-canonical TF and chromatin modifiers that feed into the IFNλ response. These studies will enhance our basic understanding of the shared and unique functions of IFN, identify cellular susceptibilities to inflammatory damage, and guide the development of therapeutic interventions that dampen excessive inflammatory responses while preserving the primordial antiviral functions of IFNs.