Human inherited complete STAT2 deficiency underlies inflammatory viral diseases

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• Signal transducer and activator of transcription 2 (STAT2) is crucial for interferon-mediated immunity.
• Loss-of-function variants in STAT2 can lead to immune dysregulation.
• Understanding STAT2's role is vital for diagnosing and managing immune deficiencies.

Purpose of the Study:

• To characterize the clinical and immunological features of autosomal recessive (AR) complete STAT2 deficiency.
• To investigate the impact of STAT2 deficiency on viral control and inflammatory responses.
• To determine the survival outcomes in patients with AR complete STAT2 deficiency.

Main Methods:

• Clinical data collection from 23 patients with AR complete STAT2 deficiency.
• In vitro studies using cells transfected with mutant STAT2 alleles.
• Analysis of IFN-stimulated gene expression and viral control.
• Transcriptomic analysis of circulating immune cells.
• Assessment of patient survival and mortality causes.

Main Results:

• Patients exhibited impaired expression of IFN-stimulated genes and reduced in vitro viral control.
• Severe adverse reactions to live attenuated viral vaccines (LAV) and severe viral infections (influenza, COVID-19, HSV-1 encephalitis) were observed.
• Hyperinflammation, involving monocytes, neutrophils, and CD8+ T cells, was a common feature, often triggered by infections or LAV.
• Significant mortality occurred, particularly in early childhood, due to viral infections or unexplained febrile illnesses.

Conclusions:

• AR complete STAT2 deficiency results in severe susceptibility to viral infections and adverse reactions to LAV.
• STAT2 is essential for effective type I and III interferon immunity and controlling viral pathogens.
• The deficiency leads to significant morbidity and mortality, highlighting the critical role of STAT2 in early life immunity and survival.