Loss of STAT2 may be dangerous in a world filled with viruses
Michael B. Jordan
Michael B. Jordan
Published June 15, 2023
Citation Information: J Clin Invest. 2023;133(12):e170886. https://doi.org/10.1172/JCI170886.
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Commentary

Loss of STAT2 may be dangerous in a world filled with viruses

Abstract

Type I IFNs, a family of cytokines that signal through a single receptor and signaling mechanism, were originally named for their ability to interfere with viral replication. While type II IFN (IFN-γ) largely protects against intracellular bacteria and protozoa, type I IFNs largely protect from viral infections. Inborn errors of immunity in humans have demonstrated this point and its clinical relevance with increasing clarity. In this issue of the JCI, Bucciol, Moens, et al. report the largest series of patients to date with deficiency of STAT2, an important protein for type I IFN signaling. Individuals with STAT2 loss demonstrated a clinical phenotype of viral susceptibility and inflammatory complications, many of which remain poorly understood. These findings further illustrate the very specific and critical role that type I IFNs play in host defense against viruses.

Authors

Michael B. Jordan

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Figure 1

STAT2 deficiency and other inborn and acquired defects of type I IFN signaling result in susceptibility to viral infections.

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STAT2 deficiency and other inborn and acquired defects of type I IFN sig...
Inborn errors of immunity affecting molecules important for type I IFN signaling, including IFNAR1, IFNAR2, TYK2, JAK1, STAT1, and IRF9, have been previously reported to cause phenotypes of severe viral infection. Bucciol, Moens, et al. (1) now report on a large series of patients with STAT2 deficiency, indicating that STAT2 loss can lead to pronounced complications with viral infections. Type I IFNs, including multiple α and β IFNs, signal through the type I IFN receptor, which utilizes the JAK/STAT signaling pathway. In addition, acquired autoantibodies against type I IFNs have been described in many patients with severe SARS-CoV-2 infection. These manifestations indicate that type I IFNs are a critical defense against frequent viral exposure. ISG, IFN-stimulated gene; PRR, pattern recognition receptor.