A Stat1 gain-of-function mutant disrupts normal Stat4 innate lymphocyte programs during viral infection [scMulti-omics-seq]

Interferonopathies drive autoimmunity but can also impair host responses to pathogens including viral infection. 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 due to excess prolonged multi-cytokine 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-γantibodies 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 response to viral infection via a normal Stat4 program was impaired, leading to overcompensated inflammatory responses in Stat1-GOF mice.