Human inherited complete STAT2 deficiency underlies inflammatory viral diseases
Giorgia Bucciol, … , Jean-Laurent Casanova, Isabelle Meyts
Giorgia Bucciol, … , Jean-Laurent Casanova, Isabelle Meyts
Published March 28, 2023
Citation Information: J Clin Invest. 2023;133(12):e168321. https://doi.org/10.1172/JCI168321.
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Research Article Immunology

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases

Abstract

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.

Authors

Giorgia Bucciol, Leen Moens, Masato Ogishi, Darawan Rinchai, Daniela Matuozzo, Mana Momenilandi, Nacim Kerrouche, Catherine M. Cale, Elsa R. Treffeisen, Mohammad Al Salamah, Bandar K. Al-Saud, Alain Lachaux, Remi Duclaux-Loras, Marie Meignien, Aziz Bousfiha, Ibtihal Benhsaien, Anna Shcherbina, Anna Roppelt, COVID Human Genetic Effort, Florian Gothe, Nadhira Houhou-Fidouh, Scott J. Hackett, Lisa M. Bartnikas, Michelle C. Maciag, Mohammed F. Alosaimi, Janet Chou, Reem W. Mohammed, Bishara J. Freij, Emmanuelle Jouanguy, Shen-Ying Zhang, Stephanie Boisson-Dupuis, Vivien Béziat, Qian Zhang, Christopher J.A. Duncan, Sophie Hambleton, Jean-Laurent Casanova, Isabelle Meyts

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Figure 3

Impact of STAT2 variants on protein production and type I IFN signaling.

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Impact of STAT2 variants on protein production and type I IFN signaling....
(A) Immunoblot of STAT2 and phosphorylated STAT2 in HEK293T cells transfected with an untagged pCMV6 expression vector containing either the WT STAT2 cDNA or 1 of the variant cDNAs in basal conditions (–) or after pretreatment with 10,000 U/mL IFN-α2A for 30 minutes (+). One representative blot from 3 experiments performed is shown. NT, not transduced; EV, empty vector. (B) Transcription levels for IFIT1, IFI27, RSAD2, and USP18 assessed by RT-qPCR on U6A fibrosarcoma cells transfected with empty vector, WT STAT2, one of the mutated alleles, or one of the homozygous variants found in gnomAD after pretreatment with 10,000 U/mL of IFN-α2B for 6 hours. The mean (n = 3) and SEM are shown. Results are normalized relative to WT unstimulated conditions. (C) Immunoblot of STAT2 and phosphorylated STAT2 in HEK293T cells transfected with an untagged pCMV6 expression vector containing either the WT STAT2 or one of the homozygous variants found in gnomAD in basal conditions (–) or after pretreatment with 10,000 U/mL IFN-α2A for 30 minutes (+). A representative blot from 2 experiments performed is shown.