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

Abstract

Although often encoding fewer than a dozen genes, RNA viruses can overcome host antiviral responses and wreak havoc on the cells they infect. Some manage to evade host antiviral defences, whereas others elicit an aberrant or disproportional immune response. Both scenarios can result in the disruption of intracellular signalling pathways and significant pathology in the host. Systems-biology approaches are increasingly being used to study the processes of viral triggering and regulation of host immune responses. By providing a global and integrated view of cellular events, these approaches are beginning to unravel some of the complexities of virus-host interactions and provide new insights into how RNA viruses cause disease.

Figure 1. Stimulation of interferon-stimulated gene expression and initiation of antiviral activity.

Pathogen-associated molecular patterns (PAMPs) in viral proteins and nucleic acids are recognized by cellular pathogen-recognition receptors (PRRs) that include RIG-I (retinoic-acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5) and certain Toll-like receptors (TLRs). PRR–PAMP interactions trigger signalling cascades that result in the activation of transcription factors, including interferon (IFN)-regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), which induce the production of type I IFNs, IFN-stimulated genes (ISGs) and pro-inflammatory cytokines and chemokines. The specific process differs between antigen-presenting cells, in which both the TLR pathway and the RIG-I or MDA5 pathway are operative, and other cell types, in which only the RIG-I or MDA5 pathway is present. Activation of PRR signalling induces an antiviral state in all cell types, and in antigen-presenting cells it can also induce the production of pro-inflammatory cytokines and chemokines. This normally results in an innate antiviral response that controls infection until it is resolved by the adaptive immune response. However, some viruses, such as the 1918 pandemic influenza virus, elicit an aberrant or disproportional response that results in immunopathology. Alternatively, viruses that suppress the type I IFN response can subvert the mechanisms of innate surveillance and diminish the potential adaptive immune response, resulting in a chronic infection. For vaccine strategies, the best induction of a broad adaptive immune response might require some degree of type I IFN response in the initial stages of infection. DCs, dendritic cells; dsRNA, double-stranded RNA; IFNAR, IFNα receptor; IL, interleukin; IPS1, IFNB-promoter stimulator 1; OAS, 2′,5′-oligoadenylate synthetase; PKR, protein kinase R; ssRNA, single-stranded RNA; STAT, signal transducer and activator of transcription; TAP1, transporter associated with antigen processing 1; TNF, tumour-necrosis factor.

Figure 2. Virus-induced gene-expression profiles in RIG-I-deficient cells.

Genomic analyses using cells that lack RIG-I (retinoic-acid-inducible gene I) show the requirement for this pathogen-recognition receptor in the induction of interferon-regulatory factor 3 (IRF3) target genes and interferon-stimulated genes (ISGs) by West Nile virus and influenza virus. a | The infection of RIG-I-deficient cells by West Nile virus results in the delay and partial inhibition of ISG expression. Deletion of MDA5 (melanoma differentiation-associated gene 5) further blocks the response to infection (not shown), indicating that the response to West Nile virus also involves MDA5. b | By contrast, the infection of RIG-I-deficient cells by influenza virus results in a near complete inhibition of ISG expression that is not further blocked by the absence of MDA5, suggesting that MDA5 does not mediate influenza virus-induced gene-expression changes. PAMPs, pathogen-associated molecular patterns. Images generated from data in Refs , .

Figure 3. Different gene-expression responses and pathology induced by contemporary and 1918 pandemic influenza virus.

In a mouse infection model, contemporary and 1918 pandemic influenza viruses each trigger an innate immune response that includes the expression of nuclear factor-κB (NF-κB) and interferon-regulatory factor 3 (IRF3) target genes. However, the gene-expression response triggered by the contemporary virus is moderate and transient and accompanied by only mild clinical symptoms. The gene-expression response to the 1918 virus is aberrantly high and sustained and may contribute to the severe clinical symptoms, including alveolitis, haemorrhage and neutrophil infiltration, that are observed in animals infected with this virus. This disproportional innate immune response and resulting immunopathology could also be the cause of the increased severity of symptoms observed in people during the 1918 pandemic. Images reproduced, with permission, from Nature Ref. © 2006 Macmillan Publishers Ltd. All rights reserved.

Figure 4. A systems-biology view of virus infection and the host response.

The benefits of functional genomics will be further enhanced by integrating genomic data with data derived from other high-throughput technologies. The potential information and biological insights provided by these technologies are shown. Together, these approaches will help to provide a systems-biology view of virus–host interactions that spans the flow of biological information from DNA (genetics) to mRNA (genomics) to protein (proteomics) to protein function (immunomics).