Interferon (IFN) responses, mediated by a myriad of IFN-stimulated genes (ISGs), are the most profound innate immune responses against viruses. Cumulatively, these IFN effectors establish a multilayered antiviral state to safeguard the host against invading viral pathogens. Considerable genetic and functional characterizations of mammalian IFNs and their effectors have been made, and our understanding on the avian IFNs has started to expand. Similar to mammalian counterparts, three types of IFNs have been genetically characterized in most avian species with available annotated genomes. Intriguingly, chickens are capable of mounting potent innate immune responses upon various stimuli in the absence of essential components of IFN pathways including retinoic acid-inducible gene I, IFN regulatory factor 3 (IRF3), and possibility IRF9. Understanding these unique properties of the chicken IFN system would propose valuable targets for the development of potential therapeutics for a broader range of viruses of both veterinary and zoonotic importance. This review outlines recent developments in the roles of avian IFNs and ISGs against viruses and highlights important areas of research toward our understanding of the antiviral functions of IFN effectors against viral infections in birds.
Individual microRNAs (miRNAs) are rapidly down-regulated during conditions of cellular activation and infection, but factors mediating miRNA turnover are poorly understood. Infection of mouse cells with murine cytomegalovirus (MCMV) induces the rapid down-regulation of an antiviral cellular miRNA, miR-27. Here, we identify a transcript produced by MCMV that binds to miR-27 and mediates its degradation. UV-crosslinking and high-throughput sequencing [CRAC (UV-crosslinking and analysis of cDNA)] identified MCMV RNA segments associated with the miRNA-binding protein Argonaute 2 (Ago2). A cluster of hits mapped to a predicted miR-27-binding site in the 3′UTR of the previously uncharacterized ORF, m169. The expression kinetics of the m169 transcript correlated with degradation of miR-27 during infection, and m169 expression inhibited miR-27 functional activity in a reporter assay. siRNA knockdown of m169 demonstrated its requirement for miR-27 degradation following infection and did not affect other host miRNAs. Substitution of the miR-27-binding site in m169 to create complementarity to a different cellular miRNA, miR-24, resulted in down-regulation of only miR-24 following infection. The m169 transcript is cytoplasmic, capped, polyadenylated, and interacts with miRNA-27 through seed pairing: characteristic features of the normal messenger RNA (mRNA) targets of miRNAs. This virus-host interaction reveals a mode of miRNA regulation in which a mRNA directs the degradation of a miRNA. We speculate that RNA-mediated miRNA degradation could be a more general viral strategy for manipulating host cells.V iruses devote a large portion of their genomes to strategies for manipulating host cells and evading antiviral defense mechanisms. Numerous host miRNA-binding sites have been predicted in different viral genomes, but the validity and functional relevance of most predictions remain unclear. The best studied miRNA-virus interactions demonstrate that RNA viruses can use cellular miRNAs to regulate their life cycles; for example, the interaction between hepatitis C virus and miR-122 enhances viral replication (1), whereas the interaction between HIV-1 and miR-29 mediates its localization to P bodies (2). Direct interactions between host miRNAs and viral genes can also suppress viral gene expression and replication (3-6) (reviewed in Ref. 7). However, the factors driving the evolution of these interactions remain somewhat controversial, because they may relate to viral mechanisms for persistence and latency rather than host defense (8, 9). At the same time, the expression levels of specific miRNAs can indirectly influence infections; miRNAs are key components of the innate immune response (10, 11) and exert antiviral properties by modulating host cofactors and pathways required by viruses (12-15). We previously showed that miR-27 limits the replication capacity of murine cytomegalovirus (MCMV) but is rapidly degraded during the lytic infection (16). Actinomycin D treatment upon infection prevents miR-27 down-regulation, suggest...
Although the functional parameters of microRNAs (miRNAs) have been explored in some depth, the roles of these molecules in viral infections remain elusive. Here we report a general method for global analysis of miRNA function that compares the significance of both overexpressing and inhibiting each mouse miRNA on the growth properties of different viruses. Our comparative analysis of representatives of all three herpesvirus subfamilies identified host miRNAs with broad anti-and proviral properties which extend to a singlestranded RNA virus. Specifically, we demonstrate the broad antiviral capacity of miR-199a-3p and illustrate that this individual hostencoded miRNA regulates multiple pathways required and/or activated by viruses, including PI3K/AKT and ERK/MAPK signaling, oxidative stress signaling, and prostaglandin synthesis. Global miRNA expression analysis further demonstrated that the miR-199a/miR-214 cluster is down-regulated in both murine and human cytomegalovirus infection and manifests similar antiviral properties in mouse and human cells. Overall, we report a general strategy for examining the contributions of individual host miRNAs in viral infection and provide evidence that these molecules confer broad inhibitory potential against multiple viruses.RNAi | herpesvirus | RNA virus | RNA processing | phosphatidylinositol-3-kinase-Akt signalling S ince the discovery of the first microRNA (miRNA) in Caenorhabditis elegans, research in diverse organisms has illuminated the role of this class of small RNA in a wide range of cellular processes (reviewed in ref.
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