Innate immune modulation by RNA viruses: emerging insights from functional genomics

Key Points By providing a global and integrated view of the host response to infection, functional genomic and systems-biology approaches are contributing to our understanding of RNA virus–host interactions. One area in which these approaches are being put to particularly good use is in shedding new light on the components of innate antiviral defence mechanisms and the viral strategies used to regulate or overcome them. Genomic analyses have helped to reveal virus-specific differences in the way that viral recognition through pathogen-recognition receptors (PRRs) initiates intracellular signalling cascades. Whereas influenza virus appears to signal primarily through retinoic-acid-inducible gene I (RIG-I), West Nile virus signals through both RIG-I and melanoma differentiation-associated gene 5 (MDA5). Both viruses induce the expression of interferon (IFN)-regulatory factor 3 (IRF3) target genes and IFN-stimulated genes (ISGs). Genomic analyses have provided a comprehensive view of the transcriptional programmes that are induced by Toll-like receptor (TLR) activation. One transcriptional profile is universally activated by all TLRs and a second profile is specific to TLR3 and TLR4. Nuclear factor-κB (NF-κB) is the key regulator of the universal response, which occurs early after TLR stimulation, and the IFN-stimulated response element (ISRE) is the key component of the TLR3/TLR4 response, which is induced after the NF-κB response. Some highly virulent viruses, such as Ebola virus and rabies virus, are successful at inhibiting ISG expression, resulting in the marked suppression of genes in key innate antiviral pathways, including those mediated by IRF3. There seems to be a correlation between the antagonism of the IFN response and virulence. Genomic analyses of the host response to the reconstructed 1918 pandemic influenza virus have revealed similarities and differences to contemporary influenza virus infection. Contemporary and 1918 influenza viruses each trigger an innate immune response that includes the expression of NF-κB and IRF3 target genes, and both viruses trigger a robust cytokine response that attracts immune-cell infiltration to infected tissues. Unlike contemporary virus strains, in which the early response to infection is resolved, the innate immune response triggered by the 1918 influenza virus is characterized by a strong and sustained induction that is associated with massive tissue damage and death. Global gene-expression profiling has re