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.
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
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.