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 6

IFN-α fails to induce ISG expression in STAT2 deficient leukocytes.

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IFN-α fails to induce ISG expression in STAT2 deficient leukocytes. (A) ...
(A) Leukocyte subsets identified by clustering analysis. PBMCs were incubated for 6 hours with or without IFN-α2b (1000 IU/mL). Variations due to batch and stimulation were integrated with Harmony (see Supplemental Methods). (B) Relative abundance of the identified cell types among PBMCs after 6 hours of incubation without (circles) and with (squares) IFN-α2b. (C) Pseudobulk PCA for leukocyte subsets. (D–F) GSEA in IFN-α2b–stimulated PBMCs from healthy controls and STAT2- and IFNAR2-deficient patients. Ranking of gene differential expression projected onto the hallmark gene sets. Immune-related gene sets were chosen for visualization. (D) IFNα2b-treated versus nonstimulated for healthy controls.(E) Relative fold-change difference in expression in the STAT2-deficient patient relative to controls for the expression changes induced by IFNα2b stimulation versus nonstimulation. (F) Relative fold-change difference in expression in the IFNAR2-deficient patient relative to controls for differences in expression induced by IFNα2b stimulation versus nonstimulation. (G) Representative volcano plots. Genes significantly up- and downregulated (FDR-adjusted P value < 0.05 and |log2FC| > 1) are shown in red and blue, respectively. (H) WGCNA. Three modules of coexpressed genes (Mod3/15/23) were induced by IFN-α2b in control cells. These modules were used for the heatmap analysis. Heatmaps show batch-corrected Z-transformed normalized pseudobulk read counts.