Genetic Lesions of Type I Interferon Signalling in Human Antiviral Immunity

Abstract

The concept that type I interferons (IFN-I) are essential to antiviral immunity derives from studies on animal models and cell lines. Virtually all pathogenic viruses have evolved countermeasures to IFN-I restriction, and genetic loss of viral IFN-I antagonists leads to virus attenuation. But just how important is IFN-I to antiviral defence in humans? The recent discovery of genetic defects of IFN-I signalling illuminates this and other questions of IFN biology, including the role of the mucosa-restricted type III IFNs (IFN-III), informing our understanding of the place of the IFN system within the concerted antiviral response. Here we review monogenic lesions of IFN-I signalling pathways and summarise the organising principles which emerge.

Keywords: IFNAR; JAK–STAT signalling; antiviral immunity; inborn errors of immunity; interferon-stimulated genes; type I interferons.

Figure 1

Canonical Interferon (IFN) Signalling Pathways and Their Genetic Lesions. Displayed are the three IFN pathways and a brief summary of the viral susceptibility phenotypes that accompany molecular defects of these pathways. IFN-I receptor (IFNAR) deficiency selectively impairs the IFN-I response, predisposing to disease secondary to inoculation with live-attenuated viral vaccines. Since IFN-I responses play a part in preventing the systemic dissemination of viruses, IFNAR-deficient individuals would hypothetically be vulnerable to arboviruses transmitted via the bloodstream. STAT2 and IRF9 are central to the response to both IFN-I and IFN-III, the latter mediating antiviral immunity at mucosal surfaces. Thus, these molecular defects are accompanied by problems in handling both live-attenuated viral vaccines and mucosally transmitted viruses such as influenza. In the case of STAT2 deficiency, variable expressivity of the phenotype is recognised. STAT1 deficiency is the most clinically serious defect since it compromises the response to all IFNs simultaneously. This is associated with susceptibility to a broad range of viruses, including herpesviruses. Because IFN-II is also critical to responses to mycobacteria, STAT1 deficiency is accompanied by life-threatening complications of mycobacterial infection. Tyrosine kinase 2 (TYK2) and (partial) Janus kinase 1 (JAK1) deficiency are also associated with mycobacterial susceptibility, alongside a much milder phenotype of viral disease. In the case of TYK2 deficiency, this may be due to the ability of IFN-III, and to a lesser extent IFN-I, to signal independently of TYK2. Complete JAK1 deficiency has not been reported. Abbreviations: CMV, cytomegalovirus; EV, enterovirus; GAF, IFNγ-activated factor; HSV, herpes simplex virus; ISGF3, interferon-stimulated gene factor 3.

Figure 2

The Extent of the Defect in the Interferon (IFN) System Correlates with Its Clinical Impact. IFN-I receptor (IFNAR) deficiency, selectively impairing IFN-I, results in susceptibility to a more limited range of viruses than signal transducer and activator of transcription (STAT)1 deficiency, which disables responses to all IFNs. STAT2 and interferon regulatory factor 9 (IRF9) deficiencies, impeding both IFN-I and IFN-III responses, are intermediate.