Novel Mechanisms Of Innate Immune Control Through RNA-binding Proteins During Viral Infection

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Type I and type III interferons (IFN) are key mediators of the innate immune response against viral infection. The more recently discovered type III IFNs (IFNL) exert antiviral protection particularly at epithelial surfaces of the respiratory and gastrointestinal tract, as well as in the liver, and they are crucial for mounting immune responses against infection with members of the Flaviviridae, such as hepatitis C virus (HCV), West Nile virus and Dengue virus. Immune genes like IFNs undergo constant regulation in order to adapt to external stimuli such as cellular stress and danger signals, and to adjust gene dosage for proper immune responses while avoiding immune pathology due to an overshooting immune system. Gene expression is tightly regulated by multilayered regulatory elements acting in both cis and trans. A powerful post-transcriptional regulatory mechanism is regulation of the mRNA 3' untranslated region (UTR), which determines the rate of translation from mRNA into protein. Prominent regulatory elements targeting the 3' UTR comprise microRNAs, RNA-binding proteins, and long noncoding RNAs, all of which alter immune gene dosage and immune response. Many immune genes such as IFNs and cytokines harbor repetitive adenylate-uridylate rich elements (AREs) consisting of at least one AUUUA pentamer in their 3' UTRs. These instability motifs are targeted by ARE-binding proteins to cause mRNA degradation, a process called ARE-mediated decay (AMD). Several genetic studies showed a strong association of the IFNL genes with spontaneous HCV clearance and response to IFN therapy. A single nucleotide polymorphism (SNP) within the 3' UTR of IFNL3 has been shown to dictate IFNL3 mRNA turnover by influencing the extent of both AMD and miRNA-mediated decay. While the HCV-induced miRNAs dictating IFNL3 mRNA instability have been identified, how the 3' UTR SNP influences IFNL3 AMD and which components are involved in this pathway is still undefined. This research proposal aims at identifying the RNA-binding protein(s) and components involved in destabilization of IFNL3 mRNA. My preliminary data suggests that the RNA-binding protein ZAP (zinc-finger antiviral protein), known as an antiviral factor targeting viral RNA, binds to and degrades host IFNL3 mRNA during HCV infection. A detailed understanding of such post-transcriptional regulatory mechanism(s) is necessary to fully understand the connection between host IFNL3 genotype and mRNA stability, the role of AMD in flaviviral immune evasion and the implications for outcome of infection. Importantly, this mechanism of immune evasion could be universal and also translate to viral infections at the epithelium of the respiratory and gastrointestinal tract (e.g. enterovirus, influenza virus, coronavirus), opening up new avenues for therapy.