Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Impaired type I interferon (IFN-I) signaling is linked to inflammatory conditions like hyperinflammation and hemophagocytic lymphohistiocytosis in patients with STAT2 or IRF9 deficiencies.
• This impairment paradoxically coexists with increased susceptibility to viral infections.

Purpose of the Study:

• To investigate the hypothesis that altered and prolonged IFN-I signaling contributes to inflammatory complications in individuals with STAT2 or IRF9 deficiencies.
• To explore the signaling kinetics and transcriptional responses in cells lacking key components of IFN-I signaling pathways.

Main Methods:

• Analysis of primary cells from individuals with complete loss of STAT1, STAT2, or IRF9.
• Utilized gene-edited induced pluripotent stem cell-derived macrophages.
• Examined signaling kinetics and transcriptional responses to IFN-α2b and IFN-γ.

Main Results:

• Deficiency in IFN-stimulated gene factor 3 components partially suppressed but prolonged IFN-I receptor signaling.
• Insufficient induction of negative regulators like USP18 was observed.
• In STAT2- and IRF9-deficient cells, late transcriptional responses to IFN-α2b mimicked IFN-γ effects.

Conclusions:

• Failure of negative feedback in IFN-I signaling due to STAT2 and IRF9 deficiency results in immune dysregulation.
• Aberrant IFN-α receptor signaling switches to a prolonged, IFN-γ-like response in deficient cells.
• This aberrant signaling likely contributes to overt inflammation in affected individuals.