The Journal of Clinical Investigation   CO M M E N TA RY

Loss of STAT2 may be dangerous in a world filled

with viruses
Michael B. Jordan
Divisions of Immunobiology and Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, University of Cincinnati Medical School, Cincinnati, Ohio, USA.

plications after receiving live attenuated

viral vaccines. Indeed, almost 70% of those
Type I IFNs, a family of cytokines that signal through a single receptor and
receiving live viral vaccines, including
signaling mechanism, were originally named for their ability to interfere
measles-mumps-rubella (MMR) and vari-
with viral replication. While type II IFN (IFN-γ) largely protects against
cella, experienced complications, such as
intracellular bacteria and protozoa, type I IFNs largely protect from viral prolonged febrile illness, encephalitis, oth-
infections. Inborn errors of immunity in humans have demonstrated er organ injury, atypical Kawasaki disease,
this point and its clinical relevance with increasing clarity. In this issue of and hemophagocytic lymphohistiocyto-
the JCI, Bucciol, Moens, et al. report the largest series of patients to date sis. Naturally occurring viral infections,
with deficiency of STAT2, an important protein for type I IFN signaling. including influenza, enterovirus, herpes
Individuals with STAT2 loss demonstrated a clinical phenotype of viral simplex, and SARS-CoV-2, also caused
susceptibility and inflammatory complications, many of which remain serious infection in a substantial fraction
poorly understood. These findings further illustrate the very specific and of these patients. Notably, though, a num-
critical role that type I IFNs play in host defense against viruses. ber of naturally occurring viral infections,
including SARS-CoV-2, were experienced
by individuals in this cohort without com-
plications. Bacterial infections were also
noted in some cases, principally pneumo-
IFN signaling and resistance to rience greater difficulties with mycobacte- nias. Approximately 40% of the patients in
viral infections rial infections (5, 6). Thus, inborn genetic this series died prematurely. Most deaths
In this issue of the JCI, Bucciol, Moens, et errors in essentially the entire proximal were during early childhood, with none
al. describe the phenotypes of an extended type I IFN-signaling pathway (Figure 1) reported after approximately four years
cohort of patients with STAT2 deficien- have demonstrated the importance of this of age. This age distribution of mortali-
cy, extending prior reports of individual pathway for resistance to a variety of virus- ty reminds one that the immune system
patients or families and giving a more com- es. As is noted by Bucciol, Moens, et al., undergoes intense virus-driven education
plete picture of human STAT2 deficien- STAT2 and related genes are under intense in the first years of life and suggests that
cy (1). In this report, 23 patients from 10 selective pressure, presumably driven by this education eventually provided pro-
families are described with biallelic loss- viruses. In recent years, it has also become tection even with defective type I IFN sig-
of-function variants in STAT2 and who increasingly appreciated that various naling. Indeed, intravenous immunoglob-
predominantly suffered from difficulty in impairments of type I IFN function, either ulins (IVIG) appeared to be therapeutic in
controlling viruses. Other inborn genetic from inborn errors or anti-IFN autoanti- some cases in the current report (1).
errors affecting the type I IFN–signaling bodies, have played an important role in
pathway, including gene defects in IFNAR1, morbidity and mortality from the SARS- Unexplained inflammatory
IFNAR2, and IRF9, have previously been CoV-2 pandemic (7, 8). Thus, increasing complications
described and cause similar difficulties evidence demonstrates that type I IFNs are In addition to severe infection, a number of
with wild viruses and live attenuated viral a critical defense against the ubiquitous inflammatory complications were notable
vaccines (1–4). Loss-of-function variants in threat that viruses pose. in this cohort. Atypical Kawasaki disease
STAT1 and partial loss-of-function of JAK1 was noted in six patients. Cytopenias and
have also been reported as causing suscep- Impact of STAT2 deficiency other clinical features consistent with sec-
tibility to viruses, but befitting their dual on viral infections ondary hemophagocytic lymphohistiocy-
role in type I and type II (IFN-γ) IFN sig- A majority of the patients studied in Bucci- tosis were observed in two patients, while
naling, patients with these variants expe- ol, Moens, et al. experienced clinical com- transient cytopenias were observed in five.
Remarkably, six patients died of heart fail-
ure in the context of febrile illness without
Related Article: https://doi.org/10.1172/JCI168321
identified pathogens. It is unclear whether
these deaths were due to viral myocarditis
Conflict of interest: MBJ receives research support and consulting fees from Sobi.
Copyright: © 2023, Jordan et al. This is an open access article published under the terms of the Creative Commons
or other unknown and/or inflammatory
Attribution 4.0 International License. etiologies. Overall, it is unclear whether
Reference information: J Clin Invest. 2023;133(12):e170886. https://doi.org/10.1172/JCI170886. these inflammatory complications were

1
CO M M E N TA RY The Journal of Clinical Investigation  

development of anticytokine antibodies,

have demonstrated that type II IFN is crit-
ical for defense against mycobacteria and
other intracellular bacterial and protozoan
pathogens, while type I IFNs play a critical
role in host defense against viruses. The
function of type III IFNs, which also rely
substantially on STAT2 for signaling, is
less clear in humans, but likely overlaps
with that of type I IFNs. Increasing hygiene
and antimicrobial drugs in the modern
world may have deceased the need to pro-
tect from various bacterial pathogens, but
viruses remain an ever-present threat and
type I IFNs are increasingly appreciated as
an essential part of our defense.

Acknowledgments
Figure 1. STAT2 deficiency and other inborn and acquired defects of type I IFN signaling result in MBJ is supported by R21CA256390 and
susceptibility to viral infections. Inborn errors of immunity affecting molecules important for type I R01FD007267.
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 Address correspondence to: Michael
patients with STAT2 deficiency, indicating that STAT2 loss can lead to pronounced complications with
Jordan, Cincinnati Children’s Hospital
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 Medical Center, 3333 Burnet Avenue,
IFNs have been described in many patients with severe SARS-CoV-2 infection. These manifestations ML 7038, Cincinnati, Ohio, USA. Phone:
indicate that type I IFNs are a critical defense against frequent viral exposure. ISG, IFN-stimulated 513.931.1676; Email: michael.jordan@
gene; PRR, pattern recognition receptor. cchmc.org.

1. Bucciol G, et al. Human inherited complete

entirely driven by abnormally severe or modality. Indeed, the lack of late deaths STAT2 deficiency underlies inflammatory viral
persistent viral infection (as viruses were in this cohort suggests that mortality risk diseases. J Clin Invest. 2023;133(12):e168321.
2. Hernandez N, et al. Inherited IFNAR1 deficiency
not always identified) or were due to an after early childhood may be low. Thus, it
in otherwise healthy patients with adverse reac-
intrinsic immune dysregulation. Indeed, is difficult to weigh the risks and benefits tion to measles and yellow fever live vaccines.
there is experimental evidence to suggest of transplantation. Despite these caveats, J Exp Med. 2019;216(9):2057–2070.
that loss of STAT2 may lead to aberrant this series suggests that one could rea- 3. Duncan CJ, et al. Human IFNAR2 deficiency:
inflammatory signaling in macrophages, sonably consider proceeding to allogeneic Lessons for antiviral immunity. Sci Transl Med.
2015;7(307):307ra154.
which is more type II IFN–like (9). There is transplantation with the identification of a
4. Hernandez N, et al. Life-threatening influenza
still much to learn regarding the pro- and very young presymptomatic patient (likely pneumonitis in a child with inherited IRF9 defi-
antiinflammatory effects of the IFNs and a sibling of a seriously affected child) who ciency. J Exp Med. 2018;215(10):2567–2585.
how these effects may be helpful or mal- has a well-matched donor graft available. 5. Le Voyer T, et al. Genetic, immunological, and
adaptive in specific contexts. In the future, with the likely widespread clinical features of 32 patients with autoso-
mal recessive STAT1 deficiency. J Immunol.
preemptive use of genetic testing, deter-
2021;207(1):133–152.
Lessons regarding care for mining the potential impact of rare muta- 6. Daza-Cajigal V, et al. Partial human Janus kinase
STAT2-deficient individuals tions in genes such as STAT2 will be of 1 deficiency predominantly impairs responses
Bucciol, Moens, et al. provide the most increasing importance for patients and the to interferon gamma and intracellular control of
complete picture of the clinical spectrum practice of medicine. mycobacteria. Front Immunol. 2022;13:888427.
7. Arrestier R, et al. Auto-antibodies against type I
of STAT2 deficiency to date. Treatment in
IFNs in > 10% of critically ill COVID-19 patients:
this cohort included high-dose IVIG and IFNs are our friends a prospective multicentre study. Ann Intensive
antiviral agents as either standard treat- in a hostile world Care. 2022;12(1):121.
ment or prophylaxis. The high mortality of In a potentially hostile world with innumer- 8. Matuozzo D, et al. Rare predicted loss-of-func-
this cohort suggests that STAT2 deficiency able viruses and ubiquitous soil and water- tion variants of type I IFN immunity genes are
associated with life-threatening COVID-19.
may be appropriately treated with bone borne bacteria with pathogenic potential,
Genome Med. 2023;15(1):22.
marrow transplantation. However, the type I and type II IFNs play an essential 9. Gothe F, et al. Aberrant inflammatory responses
curative potential for STAT2 deficiency protective role. Inborn errors of immunity to type I interferon in STAT2 or IRF9 deficiency.
has yet to be demonstrated with this risky as well as acquired impairments, such as J Allergy Clin Immunol. 2022;150(4):955–964.

2 J Clin Invest. 2023;133(12):e170886 https://doi.org/10.1172/JCI170886