Abstract
Innate antiviral immune responses are driven by virus-induced changes in host gene expression. While much research on antiviral effectors has focused on virus-inducible mRNAs, recent genome-wide analyses have identified hundreds of novel target sites for virus-inducible transcription factors and RNA polymerase. These sites are beyond the known antiviral gene repertoire and their contribution to innate immune responses is largely unknown. In this study, RNA-sequencing of mock-infected and Sendai virus-infected cells was performed to characterize the virus-inducible transcriptome and identify novel virus-inducible RNAs (nviRNAs). Virus-inducible transcription was observed throughout the genome resulting in expression of 1755 previously RefSeq-annotated RNAs and 1545 nviRNAs. The previously-annotated RNAs primarily consist of protein-coding mRNAs, including several well-known antiviral mRNAs that had low sequence conservation but were highly virus-inducible. The previously-unannotated nviRNAs were mostly noncoding RNAs with poor sequence conservation. Independent analyses of nviRNAs based on infection with Sendai virus, influenza virus, and herpes simplex virus 1, or direct stimulation with IFNα revealed a range of expression patterns in various human cell lines. These phylogenetic and expression analyses suggest that many of the nviRNAs share the high inducibility and low sequence conservation characteristic of well-known primary antiviral effectors and may represent dynamically evolving antiviral factors.
Highlights
The most widely studied virus-induced RNAs encode effector proteins that mediate virus interference and signal amplification[5], including several types of interferon (IFN), antiviral cytokines that are secreted from the infected cells[6]
To fully appreciate the extent of virus-induced RNA transcription, human Namalwa B cells were infected with Sendai virus, an RNA virus that is a potent inducer of antiviral signaling[22]
Enrichment of RNAs in mock-infected or virus-infected samples was analysed with the DESeq[2] program, resulting in the identification of 6210 RNAs that were differentially expressed after virus infection at a false discovery rate (FDR) of 5% and fold change of at least 1.5
Summary
The most widely studied virus-induced RNAs encode effector proteins that mediate virus interference and signal amplification[5], including several types of interferon (IFN), antiviral cytokines that are secreted from the infected cells[6]. In the case of lncRNA-ACOD1, expression promotes rather than interferes with virus replication by regulating cellular metabolism[21] These examples underscore the importance of deep sequencing approaches to characterize the extent of noncoding RNA transcription following virus infections. Analysis of newly-identified virus-induced RNAs, referred to here as nviRNAs22, reveals that they can be induced by RNA and DNA-genome viruses as well as by direct stimulation with the type I IFN, IFNα, in both general and cell-specific fashion. These findings expand the extent of virus-induced transcription and suggest that both coding and noncoding RNA expression are hallmarks of the cellular response to virus infections
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