Human inherited complete STAT2 deficiency underlies inflammatory viral diseases.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Bucciol Giorgia, Moens Leen, Ogishi Masato, Rinchai Darawan, Matuozzo Daniela, Momenilandi Mana, Kerrouche Nacim, Cale Catherine M, Treffeisen Elsa R, Al Salamah Mohammad, Al-Saud Bandar K, Lachaux Alain, Duclaux-Loras Remi, Meignien Marie, Bousfiha Aziz, Benhsaien Ibtihal, Shcherbina Anna, Roppelt Anna, COVID Human Genetic Effort, Gothe Florian, Houhou-Fidouh Nadhira, Hackett Scott J, Bartnikas Lisa M, Maciag Michelle C, Alosaimi Mohammed F, Chou Janet, Mohammed Reem W, Freij Bishara J, Jouanguy Emmanuelle, Zhang Shen-Ying, Boisson-Dupuis Stephanie, Béziat Vivien, Zhang Qian, Duncan Christopher Ja, Hambleton Sophie, Casanova Jean-Laurent, Meyts Isabelle
Аннотация
STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.