{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:40:24Z","timestamp":1790746824667,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["207556\/Z\/17\/Z, 211153\/Z\/18\/Z"],"award-info":[{"award-number":["207556\/Z\/17\/Z, 211153\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>STAT2 is a transcription factor that plays an essential role in antiviral immunity by mediating the activity of type I and III interferons (IFN-I and IFN-III). It also has a recently established function in the negative regulation of IFN-I signaling. Homozygous STAT2 deficiency is an ultra-rare inborn error of immunity which provides unique insight into the pathologic consequence of STAT2 dysfunction. We report here a novel genetic cause of homozygous STAT2 deficiency with several notable clinical features. The proband presented aged 12 months with hemophagocytic lymphohistiocytosis (HLH) closely followed by clinical varicella, both occurring within three weeks of measles, mumps, and rubella (MMR) and varicella vaccinations. There was a history of life-threatening influenza A virus (IAV) disease 2 months previously. Genetic investigation uncovered homozygosity for a novel nonsense variant in <jats:italic>STAT2<\/jats:italic> (c. 1999C&amp;gt;T, p. Arg667Ter) that abrogated STAT2 protein expression. Compatible with STAT2 deficiency, dermal fibroblasts from the child demonstrated a defect of interferon-stimulated gene expression and a failure to mount an antiviral state in response to treatment with IFN-I, a phenotype that was rescued by lentiviral complementation by wild type <jats:italic>STAT2<\/jats:italic>. This case significantly expands the phenotypic spectrum of STAT2 deficiency. The occurrence of life-threatening influenza, which has not previously been reported in this condition, adds <jats:italic>STAT2<\/jats:italic> to the list of monogenetic causes of this phenotype and underscores the critical importance of IFN-I and IFN-III to influenza immunity. The development of probable vaccine-strain varicella is also a novel occurrence in STAT2 deficiency, implying a role for IFN-I\/III immunity in control of attenuated varicella zoster virus <jats:italic>in vivo<\/jats:italic> and reinforcing the susceptibility to pathologic effects of live-attenuated viral vaccines in disorders of IFN-I immunity. Finally, the occurrence of HLH in this case reinforces emerging links to hyperinflammation in patients with STAT2 deficiency and other related defects of IFN-I signaling\u2014highlighting an important avenue for further scientific enquiry.<\/jats:p>","DOI":"10.3389\/fimmu.2020.624415","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T19:36:34Z","timestamp":1613849794000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Life-Threatening Influenza, Hemophagocytic Lymphohistiocytosis and Probable Vaccine-Strain Varicella in a Novel Case of Homozygous STAT2 Deficiency"],"prefix":"10.3389","volume":"11","author":[{"given":"Bishara J.","family":"Freij","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan T.","family":"Hanrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Hambleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J. A.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"B1","article-title":"Genetic Lesions of Type I Interferon Signalling in Human Antiviral Immunity","author":"Duncan","year":"2020","journal-title":"Trends Genet"},{"key":"B2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.coi.2019.12.002","article-title":"Recent human genetic errors of innate immunity leading to increased susceptibility to infection","volume":"62","author":"Moens","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"B3","doi-asserted-by":"crossref","first-page":"eabd4570","DOI":"10.1126\/science.abd4570","article-title":"Inborn errors of type I IFN immunity in patients with life-threatening COVID-19","volume":"370","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"B4","doi-asserted-by":"crossref","first-page":"eabd4585","DOI":"10.1126\/science.abd4585","article-title":"Autoantibodies against type I IFNs in patients with life-threatening COVID-19","volume":"370","author":"Bastard","year":"2020","journal-title":"Science"},{"key":"B5","article-title":"Virus interference. I. The interferon. Proceedings of the Royal Society of London","volume":"147","author":"Isaacs","year":"1957","journal-title":"Ser B Biol Sci"},{"key":"B6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/ni875","article-title":"IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex","volume":"4","author":"Kotenko","year":"2003","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.1038\/ni873","article-title":"IL-28, IL-29 and their class II cytokine receptor IL-28R","volume":"4","author":"Sheppard","year":"2003","journal-title":"Nat Immunol"},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1038\/ng.2521","article-title":"A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus","volume":"45","author":"Prokunina-Olsson","year":"2013","journal-title":"Nat Genet"},{"key":"B9","doi-asserted-by":"crossref","first-page":"e1000017","DOI":"10.1371\/journal.ppat.1000017","article-title":"IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo","volume":"4","author":"Sommereyns","year":"2008","journal-title":"PLoS Pathog"},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1220098110","article-title":"STAT2 deficiency and susceptibility to viral illness in humans","volume":"110","author":"Hambleton","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1016\/j.jaci.2016.10.033","article-title":"A novel kindred with inherited STAT2 deficiency and severe viral illness","volume":"139","author":"Moens","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.jaci.2019.05.008","article-title":"A novel variant in STAT2 presenting with hemophagocytic lymphohistiocytosis","volume":"144","author":"Alosaimi","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr Blood Cancer"},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.1038\/nsmb.3378","article-title":"STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling","volume":"24","author":"Arimoto","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.1074\/jbc.M109078200","article-title":"UBP43 (USP18) specifically removes ISG15 from conjugated proteins","volume":"277","author":"Malakhov","year":"2002","journal-title":"J Biol Chem"},{"key":"B16","doi-asserted-by":"crossref","DOI":"10.1128\/MCB.00224-09","article-title":"Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18\/UBP43","volume":"29","author":"Sarasin-Filipowicz","year":"2009","journal-title":"Mol Cell Biol"},{"key":"B17","doi-asserted-by":"crossref","first-page":"e22200","DOI":"10.1371\/journal.pone.0022200","article-title":"USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon alpha response","volume":"6","author":"Francois-Newton","year":"2011","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"crossref","DOI":"10.1038\/sj.emboj.7601149","article-title":"UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity","volume":"25","author":"Malakhova","year":"2006","journal-title":"EMBO J"},{"key":"B19","doi-asserted-by":"crossref","first-page":"e2000117","DOI":"10.1371\/journal.pbio.2000117","article-title":"STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways","volume":"14","author":"Ho","year":"2016","journal-title":"PLoS Biol"},{"key":"B20","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aav7501","article-title":"Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2","volume":"4","author":"Duncan","year":"2019","journal-title":"Sci Immunol"},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20192319","article-title":"Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy","volume":"217","author":"Gruber","year":"2020","journal-title":"J Exp Med"},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.1016\/j.coi.2015.12.002","article-title":"Host genetics of severe influenza: from mouse Mx1 to human IRF7","volume":"38","author":"Ciancanelli","year":"2016","journal-title":"Curr Opin Immunol"},{"key":"B23","doi-asserted-by":"crossref","DOI":"10.1126\/science.aaa1578","article-title":"Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency","volume":"348","author":"Ciancanelli","year":"2015","journal-title":"Science"},{"key":"B24","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20180628","article-title":"Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency","volume":"215","author":"Hernandez","year":"2018","journal-title":"J Exp Med"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20181621","article-title":"Severe influenza pneumonitis in children with inherited TLR3 deficiency","volume":"216","author":"Lim","year":"2019","journal-title":"J Exp Med"},{"key":"B26","doi-asserted-by":"crossref","DOI":"10.1101\/gr.3715005","article-title":"Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes","volume":"15","author":"Siepel","year":"2005","journal-title":"Genome Res"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.1038\/nmeth0810-575","article-title":"MutationTaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat Methods"},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"crossref","DOI":"10.1016\/S0264-410X(00)00297-8","article-title":"The postmarketing safety profile of varicella vaccine","volume":"19","author":"Sharrar","year":"2000","journal-title":"Vaccine"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1016\/j.vaccine.2010.06.056","article-title":"Safety profile of live varicella virus vaccine (Oka\/Merck): five-year results of the European Varicella Zoster Virus Identification Program (EU VZVIP)","volume":"28","author":"Goulleret","year":"2010","journal-title":"Vaccine"},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1126\/science.1139522","article-title":"TLR3 deficiency in patients with herpes simplex encephalitis","volume":"317","author":"Zhang","year":"2007","journal-title":"Science"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1172\/JCI139980","article-title":"Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency","volume":"131","author":"Bastard","year":"2021","journal-title":"J Clin Invest"},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20182295","article-title":"Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines","volume":"216","author":"Hernandez","year":"2019","journal-title":"J Exp Med"},{"key":"B35","doi-asserted-by":"crossref","first-page":"307ra154","DOI":"10.1126\/scitranslmed.aac4227","article-title":"Human IFNAR2 deficiency: Lessons for antiviral immunity","volume":"7","author":"Duncan","year":"2015","journal-title":"Sci Transl Med"},{"key":"B36","doi-asserted-by":"crossref","DOI":"10.1056\/NEJMoa0907206","article-title":"Inflammatory bowel disease and mutations affecting the interleukin-10 receptor","volume":"361","author":"Glocker","year":"2009","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00272-10","article-title":"Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections","volume":"84","author":"Mordstein","year":"2010","journal-title":"J Virol"},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.33354","article-title":"IFN-lambda prevents influenza virus spread from the upper airways to the lungs and limits virus transmission","volume":"7","author":"Klinkhammer","year":"2018","journal-title":"Elife"},{"key":"B39","doi-asserted-by":"crossref","DOI":"10.1016\/j.jinf.2015.04.015","article-title":"Varicella zoster virus immunity: A primer","author":"Duncan","year":"2015","journal-title":"J Infect"},{"key":"B40","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.jaci.2019.02.019","article-title":"Impaired control of multiple viral infections in a family with complete IRF9 deficiency","volume":"144","author":"Bravo Garcia-Morato","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B41","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaip.2016.02.015","article-title":"A novel presentation of homozygous loss-of-function STAT-1 mutation in an infant with hyperinflammation-A case report and review of the literature","volume":"4","author":"Burns","year":"2016","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B42","doi-asserted-by":"crossref","DOI":"10.1016\/j.immuni.2011.02.006","article-title":"Type I interferon inhibits interleukin-1 production and inflammasome activation","volume":"34","author":"Guarda","year":"2011","journal-title":"Immunity"},{"key":"B43","doi-asserted-by":"crossref","DOI":"10.1126\/science.1254790","article-title":"Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon","volume":"345","author":"Reboldi","year":"2014","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.624415\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T06:37:14Z","timestamp":1613975834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.624415\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,18]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2020.624415"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.624415","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,18]]},"article-number":"624415"}}