Genetic Lesions of Type I Interferon Signalling in Human Antiviral Immunity.

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. Inborn errors of immunity affecting all key molecular components of the interferon (IFN)-I signalling pathway [IFN-alpha/beta receptor (IFNAR)1, IFNAR2, Janus kinase 1 (JAK1), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription (STAT)1, STAT2, and interferon regulatory factor 9 (IRF9)] have been identified in humans. Deficiency of IFNAR results in potentially fatal susceptibility to live-attenuated viral vaccines, but without general susceptibility to common childhood viral diseases. Clinically evident vulnerability to a broader spectrum of viral diseases, including respiratory viruses such as influenza as well as live-attenuated viral vaccines, often accompanies deficiency of STAT2 and IRF9. These molecules transduce signals downstream of IFN-I and IFN-III, suggesting that the latter provides compensatory antiviral defence in IFNAR-deficient patients. Children with defects in IFN-I and IFN-III signalling are not particularly susceptible to viruses such as cytomegalovirus (CMV), suggesting that this virus has successfully evolved mechanisms to overcome IFN-I/III restriction. STAT1-deficient patients, who lack signalling in response to all types of IFN (I, II, and III), show the widest viral susceptibility of all. Pathological dissemination of parenterally delivered live-viral vaccines in otherwise healthy children should signify an inborn error of IFN-I immunity until proved otherwise. [ABSTRACT FROM AUTHOR]