An activating <i>Stat1</i> mutant disrupts normal STAT4 innate lymphocyte programs during viral infection
Interferonopathies drive autoimmunity but can also impair host responses to pathogens, including viral infections. To better understand viral susceptibility of patients with <i>STAT1</i> gain-of-function (GOF) mutations, we generated conditional knockin mouse models to elucidate disease mechanisms and relevance of different immune subsets. Virally infected <i>Stat1</i> GOF mice exhibited impaired early IFN-γ production from innate lymphocytes and lethality because of excess prolonged multicytokine production. The presence of the <i>Stat1</i> GOF allele resulted in premature usage of interferon-stimulated gene factor 3 (ISGF3) over the normal STAT4-AP-1-dependent transcriptomic program in activated innate lymphocytes. Administration of anti-IFN-γ antibodies in wild-type (WT) mice after infection phenocopied <i>Stat1</i> GOF mice presenting exaggerated inflammation despite viral control. Conversely, early administration of exogenous IFN-γ to infected <i>Stat1</i> GOF mice prevented lethality and exaggerated cytokine response. Although <i>Stat1</i> GOF mutations facilitate IFN-γ-mediated autoimmunity, early IFN-γ responses to viral infection via a normal STAT4 program were impaired, leading to overcompensated inflammatory responses in <i>Stat1</i> GOF mice.
Authors
- Joshua D. Milner (ORCID: https://orcid.org/0000-0002-3913-3869)
- Yuka Kanno (ORCID: https://orcid.org/0000-0001-5668-9319)
- Michail S. Lionakis (ORCID: https://orcid.org/0000-0003-4994-9500)
- Heather D. Hickman (ORCID: https://orcid.org/0000-0003-4168-4894)
- Steven M. Holland (ORCID: https://orcid.org/0000-0003-3207-5464)
- Kan Jiang (ORCID: https://orcid.org/0009-0002-1402-0355)
- John J. O’Shea (ORCID: https://orcid.org/0000-0002-6456-9752)
- Joseph Chai-Yuen Sun (ORCID: https://orcid.org/0000-0001-8062-9033)
- Rachael L. Philips (ORCID: https://orcid.org/0000-0001-5440-4594)
- Colleen M. Lau (ORCID: https://orcid.org/0000-0001-7538-094X)
- Chen Yao (ORCID: https://orcid.org/0000-0001-6852-5661)
- Yi-Chu Liao (ORCID: https://orcid.org/0000-0002-9458-1445)
- Tasha Morrison (ORCID: https://orcid.org/0000-0002-6403-9364)
- Justin Shayne (ORCID: https://orcid.org/0009-0003-5617-6494)
- Andrew T. Hutchinson
Institutions
- National Institutes of Health (US)
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Columbia University Irving Medical Center (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- Office of Extramural Research (US)
- New York State College of Veterinary Medicine (US)
- National Institute of General Medical Sciences (US)
- National Institute of Mental Health (US)
- Organogenesis (United States) (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1126/sciimmunol.ado5986
- Citations
- 2
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 2.09