{"doi":"10.1126/sciimmunol.ado5986","title":"An activating <i>Stat1</i> mutant disrupts normal STAT4 innate lymphocyte programs during viral infection","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.","journal":"Science Immunology","year":2025,"id":533800,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1415982,"name":"Yi-Chu Liao","orcid":"0000-0002-9458-1445","position":1,"is_corresponding":false},{"id":322860,"name":"Colleen M. Lau","orcid":"0000-0001-7538-094X","position":2,"is_corresponding":false},{"id":313438,"name":"Tasha Morrison","orcid":"0000-0002-6403-9364","position":3,"is_corresponding":false},{"id":844373,"name":"Kan Jiang","orcid":"0000-0001-9065-4574","position":4,"is_corresponding":false},{"id":1416432,"name":"Amal Hutchinson","orcid":null,"position":5,"is_corresponding":false},{"id":1237537,"name":"Justin Shayne","orcid":"0009-0003-5617-6494","position":6,"is_corresponding":false},{"id":39928,"name":"Chen Yao","orcid":"0000-0001-6852-5661","position":7,"is_corresponding":false},{"id":61584,"name":"Joseph C. Sun","orcid":"0000-0001-8062-9033","position":8,"is_corresponding":false},{"id":245858,"name":"Heather D. Hickman","orcid":"0000-0003-4168-4894","position":9,"is_corresponding":false},{"id":225938,"name":"Joshua D. Milner","orcid":"0000-0002-3913-3869","position":10,"is_corresponding":false},{"id":104227,"name":"Steven M. Holland","orcid":"0000-0003-3207-5464","position":11,"is_corresponding":false},{"id":291947,"name":"Yuka Kanno","orcid":"0000-0001-5668-9319","position":12,"is_corresponding":false},{"id":104225,"name":"Michail S. Lionakis","orcid":"0000-0003-4994-9500","position":13,"is_corresponding":false},{"id":291946,"name":"John J. O’Shea","orcid":"0000-0002-6456-9752","position":14,"is_corresponding":false},{"id":677208,"name":"Rachael L. Philips","orcid":"0000-0001-5440-4594","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:51:43.451278Z","pmid":"40446018","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}