An activating Stat1 mutant disrupts normal STAT4 innate lymphocyte programs during viral infection 2025 O'Shea et al

Editor’s summary

Human gain of function (GOF) mutations in STAT1—a critical signaling molecule downstream of interferons (IFNs)—result in excessive IFN responses and autoimmune disease. Patients with STAT1 GOF mutations are also prone to certain fungal, mycobacterial, and viral infections.

However, Philips et al. generated mouse lines expressing the human pathogenic Stat1T385M GOF mutation in a tissue-specific manner. Although these mice had IFN-γ–dependent autoimmune disease, their innate-like lymphocyte populations produced insufficient IFN-γ during viral infection because of premature usage of ISGF3 over a STAT4–AP-1–dependent transcriptomic program. This led to poor outcomes because optimal IFN-γ is needed to regulate antiviral inflammation. Administration of exogenous IFN-γ to Stat1 GOF mice prevented virus-induced lethality, suggesting a possible therapeutic approach for patients with these mutations. —Seth Thomas Scanlon

Abstract

Interferonopathies drive autoimmunity but can also impair host responses to pathogens, including viral infections. To better understand viral susceptibility of patients with STAT1 gain-of-function (GOF) mutations, we generated conditional knockin mouse models to elucidate disease mechanisms and relevance of different immune subsets.

Virally infected Stat1 GOF mice exhibited impaired early IFN-γ production from innate lymphocytes and lethality because of excess prolonged multicytokine production. The presence of the Stat1 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 Stat1 GOF mice presenting exaggerated inflammation despite viral control. Conversely, early administration of exogenous IFN-γ to infected Stat1 GOF mice prevented lethality and exaggerated cytokine response.

Although Stat1 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 Stat1 GOF mice.

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