The rabies virus interferon antagonist P protein selectively modulates interferon signalling to inhibit antiviral gene expression while supporting proviral gene expression

Type-I IFNs mediate the principle antiviral response of cells by controlling the expression of hundreds of IFN-regulated genes (IRGs), many of which have antiviral functions. The best understood mediators of IFN signalling are STAT1 and STAT2, and STAT1/2-dependent gene induction is conventionally viewed as the primary outcome of type-I IFN signalling. To overcome the IFN response, viruses express proteins called IFN-antagonists, which target IFN signalling pathways (e.g. rabies virus P-protein (RABV-P) binds and inhibits IFN-activated STAT1/2) and so are typically considered to mediate shutdown of the IFN response. However, IFN signalling is not exclusively antiviral, with many IRGs reported to be required for or to facilitate infection by certain viruses. How viruses coordinate the apparent need to suppress certain antiviral IRGs, while presumably permitting the expression of others, including proviral IRGs is poorly defined. However, it has been shown that type-I IFN can activate multiple pathways other than classical STAT1/2, so discriminatory targeting of specific pathways by IFN-antagonists may enable highly selective regulation of distinct IRGs, dependent on the requirements of the specific virus. Here, we analyse the global effects of RABV-P protein on the IFN-regulated transcriptome. We confirm that IFN not only stimulates (IFN-stimulated genes, ISGs) but also represses (IFN-repressed genes, IRepGs) a large number of IRGs. Notably, our data indicate that RABV-P protein can antagonize both the IFN-dependent stimulation and repression of certain ISGs and IRepGs, without significantly impacting the expression of large proportion of IRGs. Antagonized ISGs included classical antiviral genes, while non-antagonized ISGs include genes with pro-viral effects on RABV. Transcription factor analysis indicated that RABV-P antagonizes STAT1/2-regulated IRGs, but not IRGs regulated by other pathways including MAP-kinase pathways, which are important to process such as cell survival and inflammatory response. These data indicate that selective modulation rather than global inhibition of IFN-signalling has beneficial outcomes for replication. The data also support the significance of IRepGs, and their modulation by IFN antagonists in viral infection. Significance StatementThe ability of viruses to evade immunity is critical to disease and so presents targets for the development of interventions. The principle antiviral response of cells is mediated by interferons (IFNs), which activate STAT proteins to induce hundreds of genes including antiviral genes. Viruses counter this by expressing IFN-antagonist proteins, many of which directly inhibit STATs. IFN-antagonists are typically considered to shut down IFN responses, but many IRGs have pro-viral functions. How viruses coordinate the apparent need to antagonise some IRGs but not others are poorly understood. Using a well-characterised viral IFN-antagonist, we find that by selectively targeting certain IFN-activated pathways, IFN-antagonists can inhibit effects of IFN on specific subsets of IRGs (including antiviral genes) without affecting others (including proviral genes); thus, IFN-antagonists may be redefined as selective IFN-modulators.