An activating Stat1 mutant disrupts normal STAT4 innate lymphocyte programs during viral infection

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Interferonopathies, including STAT1 gain-of-function (GOF) mutations, are linked to autoimmunity and impaired responses to pathogens.
• Understanding the mechanisms of viral susceptibility in patients with STAT1 GOF mutations is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the mechanisms underlying viral susceptibility in STAT1 GOF mutations.
• To elucidate the role of different immune subsets in the pathogenesis of STAT1 GOF-associated viral infections.
• To evaluate the therapeutic potential of interferon-gamma (IFN-γ) in STAT1 GOF mice.

Main Methods:

• Generated conditional knockin mouse models for STAT1 GOF mutations.
• Infected mice with viruses and analyzed immune responses, including cytokine production and transcriptomic programs.
• Administered anti-IFN-γ antibodies or exogenous IFN-γ to assess therapeutic effects.

Main Results:

• STAT1 GOF mice exhibited impaired early IFN-γ production from innate lymphocytes and lethal multicytokine overproduction upon viral infection.
• The STAT1 GOF allele led to premature ISGF3 pathway activation over the normal STAT4-AP-1 program in innate lymphocytes.
• Anti-IFN-γ treatment in wild-type mice mimicked STAT1 GOF pathology, while early IFN-γ administration protected STAT1 GOF mice from lethality.

Conclusions:

• STAT1 GOF mutations impair protective early IFN-γ responses to viral infections, leading to overcompensated inflammation and lethality.
• Targeting IFN-γ signaling pathways may offer therapeutic benefits for patients with STAT1 GOF mutations experiencing viral infections.