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Fatal COVID-19 Infection in Two Children with STAT1 Gain-of-Function

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Abstract

While SARS-CoV-2 infection causes a mild disease in most children, SARS-CoV-2 infection may be lethal in a few of them. In the defense against SARS-CoV-2, type I interferons are key players, and several studies have identified a defective or neutralized interferon response as the cause of overwhelming viral infection. However, inappropriate, untimely, or excessive interferon production may also be detrimental to the host. Here, we describe two patients with STAT1 gain-of-function (GOF), a known type I interferonopathy, who died of COVID-19. Whole-exome sequencing and interferon-gamma-activated sequence (GAS) and interferon-sensitive responsive element (ISRE) reporter assay were performed to identify and characterize STAT1 variants. Patient 1 developed hemophagocytic lymphohistiocytosis (HLH) in the context of COVID-19 infection and died in less than a week at the age of 4 years. Patient 2 developed a high fever, cough, and hypoxemia and succumbed to COVID-19 pneumonia at the age of 5 years. Two heterozygous missense variants, p.E563Q and p.K344E, in STAT1 were identified. Functional validation by reporter assay and immunoblot confirmed that both variants are gain-of-function (GOF). GOF variants transiently expressing cells exhibited enhanced upregulation of downstream genes, including ISG15, MX1, and OAS1, in response to IFN-α stimulation. A catastrophic course with HLH or acute respiratory failure is thought to be associated with inappropriate immunoregulatory mechanisms to handle SARS-CoV-2 in STAT1 GOF. While most patients with inborn errors of immunity who developed COVID-19 seem to handle it well, these cases suggest that patients with STAT1-GOF might be at risk of developing fatal complications due to SARS-CoV-2.

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Data Availability

The data that support the findings of this study are available from the corresponding authors.

Abbreviations

COVID-19:

Coronavirus disease 2019

DNA:

Deoxyribonucleic acid

GOF:

Gain-of-function

HIV:

Human immunodeficiency virus

HLH:

Hemophagocytic lymphohistiocytosis

IFN:

Interferon

IEI:

Inborn error of immunity

MAS:

Macrophage activation syndrome

MIS-C:

Multisystem inflammatory syndrome in children

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

STAT1:

Signal transducer and activator of transcription 1

RT-PCR:

Real-time polymerase chain reaction

WES:

Whole-exome sequencing

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Acknowledgements

ATSB, GGF, and SOLR thank Dr. Sara Elva Espinosa Padilla for the useful clinical discussions.

Funding

PV received funding from the Science and Engineering Research Board, Government of India (SRG/2019/002264), for his research project entitled, Identification of Immunogenetic Risk Factors for Serious Fungal Infections in Children- a Next-Generation Sequencing based Study. This work was partially supported by MEXT/JSPS KAKENHI (Grant Number: 19H03620, 22H03041, and 22KK0113) and AMED (Grant Number: JP21fk0108436 andJP22fk0108514 and) to SO.

Author information

Authors and Affiliations

  1. Immunology Service at Hospital de Especialidades UMAE 25 Mexican Social Security, Institute (IMSS), Monterrey, Mexico

    Aidé Tamara Staines-Boone & Yuridia Salazar-Gálvez

  2. Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Pandiarajan Vignesh, Reva Tyagi, Amit Rawat & Jhumki Das

  3. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, Hiroshima, Japan

    Miyuki Tsumura, Takaki Asano & Satoshi Okada

  4. Immune Deficiencies Laboratory at the National Institute of Pediatrics, Health Secretariat, Av Iman 1, Piso 9 Torre de Investigación, Col. Insurgentes Cuicuilco, Coyoacán, 04530, Mexico City, CDMX, Mexico

    Germán de la Garza Fernández & Saul O Lugo Reyes

  5. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Dan Tomomasa

  6. School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    Atsushi Hijikata

  7. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Hirokazu Kanegane

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  1. Aidé Tamara Staines-Boone
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  2. Pandiarajan Vignesh
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Contributions

ATSB cared for patient 1, suspected an inborn error of immunity, collected data, supplied biological samples, and approved the final version of the manuscript.

PV and RT cared for patient 2, collected data, and approved the final version.

AR carried out necessary immunological assays and next-generation sequencing and analysis using a targeted 44 PID gene panel for patient 2.

MT performed luciferase reporter assays and read and approved the final version.

TA computed the CADD/MAFF scores, prepared supplementary Fig. 3, helped in critical review and final approval of the manuscript.

DT performed in silico analysis of the variants and approved the final version.

AH performed structural analysis of the STAT1 protein and approved the final version.

YSG also cared for patient 1, collected data, and approved the final version of the manuscript.

HK liaised with the clinical teams, edited the manuscript, and approved the final version.

GGF reviewed the medical chart of patient 1, wrote the first and second drafts of the case report, and approved the final version.

SO conceived the manuscript, liaised with the clinical teams, supervised the functional validation of the variants, corrected, edited, and approved the final version.

SOLR analyzed the exome of patient 1, conceived the manuscript and wrote and edited the second and final drafts.

Corresponding authors

Correspondence to Pandiarajan Vignesh, Satoshi Okada or Saul O Lugo Reyes.

Ethics declarations

Ethical/IRB Approval Statement

This study was performed in line with the principles of the Declaration of Helsinki. Patients or their guardians consented in writing to their genetic evaluation and the publication of these case reports. The study was approved by the Institutional Review Board of the National Institute of Pediatrics (number 2013/049).

Consent to Participate

Written informed consent was obtained from the parents.

Consent for Publication

Consent for publication was given by the patients’ family members.

Conflict of Interest

The authors declare no competing interests.

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Aidé Tamara Staines-Boone, Pandiarajan Vignesh and Miyuki Tsumura contributed equally to this study and share first authorship.

Pandiarajan Vignesh,  Satoshi Okada and Saul O Lugo Reyes contributed equally and share senior authorship.

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Staines-Boone, A.T., Vignesh, P., Tsumura, M. et al. Fatal COVID-19 Infection in Two Children with STAT1 Gain-of-Function. J Clin Immunol 44, 20 (2024). https://doi.org/10.1007/s10875-023-01634-0

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