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BACKGROUND: Inflammatory phenomena such as hyperinflammation or hemophagocytic lymphohistiocytosis are a frequent yet paradoxical accompaniment to viral susceptibility in patients with impairment of type I interferon (IFN-I) signaling caused by deficiency of STAT2 or IRF9. OBJECTIVE: We hypothesized that altered and/or prolonged IFN-I signaling contributes to inflammatory complications in these patients. METHODS: We explored the signaling kinetics and residual transcriptional responses of IFN-stimulated primary cells from individuals with complete loss of either STAT1, STAT2 or IRF9 as well as gene-edited iPSC-derived macrophages. RESULTS: Deficiency of any ISGF3 component suppressed but did not abrogate IFN-I receptor signaling, which was abnormally prolonged in keeping with insufficient induction of negative regulators such as USP18. In cells lacking either STAT2 or IRF9, this late transcriptional response to IFNα2b mimicked the effect of IFNγ. CONCLUSION: Our data suggest a model wherein the failure of negative feedback of IFN-I signaling in STAT2 and IRF9 deficiency leads to immune dysregulation. Aberrant IFNAR signaling in STAT2- and IRF9-deficient cells switches the transcriptional output to a prolonged, IFNγ-like response and likely contributes to clinically overt inflammation in these individuals.

Original publication




Journal article


J Allergy Clin Immunol

Publication Date



GAF, HLH, IRF9, ISGF3, STAT2, Type I interferon, antiviral immunity, type II interferon