Altered increase in STAT1 expression and phosphorylation in severe COVID-19.

Abstract

The interferon pathway, a key antiviral defense mechanism, is being considered as a therapeutic target in COVID-19. Both, substitution of interferon and JAK/STAT inhibition to limit cytokine storms have been proposed. However, little is known about possible abnormalities in STAT signaling in immune cells during SARS-CoV-2 infection. We investigated downstream targets of interferon signaling, including STAT1, STAT2, pSTAT1 and 2, and IRF1, 7 and 9 by flow cytometry in 30 patients with COVID-19, 17 with mild, and 13 with severe infection. We report upregulation of STAT1 and IRF9 in mild and severe COVID-19 cases, which correlated with the IFN-signature assessed by Siglec-1 (CD169) expression on peripheral monocytes. Interestingly, Siglec-1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe cases compared to mild cases. Contrary to the baseline STAT1 expression, the phosphorylation of STAT1 was enhanced in severe COVID-19 cases, indicating a dysbalanced JAK/STAT signaling that fails to induce transcription of interferon stimulated response elements (ISRE). This abnormality persisted after IFN-α and IFN-γ stimulation of PBMCs from patients with severe COVID-19. Data suggest impaired STAT1 transcriptional upregulation among severely infected patients may represent a potential predictive biomarker and would allow stratification of patients for certain interferon-pathway targeted treatments.

• Authors: Hector Rincon-Arevalo, Arman Aue, Jacob Ritter, Franziska Szelinski, Dmytro Khadzhynov, Daniel Zickler, Luisa Stefanski, Andreia C Lino, Sixten Körper, Kai-Uwe Eckardt, Hubert Schrezenmeier, Thomas Dörner, Eva V Schrezenmeier
• Journal: European journal of immunology (Eur J Immunol) Vol. 52 Issue 1 Pg. 138-148 (01 2022) ISSN: 1521-4141 [Electronic] Germany
• PMID: 34676541 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.

Chemical References

• Interferon Regulatory Factors
• STAT1 Transcription Factor
• STAT1 protein, human

Topics

• Adult
• Aged
• COVID-19 (immunology)
• Female
• Humans
• Interferon Regulatory Factors (immunology)
• Male
• Middle Aged
• Monocytes (immunology)
• Patient Acuity
• Phosphorylation (immunology)
• SARS-CoV-2 (immunology)
• STAT1 Transcription Factor (immunology)
• Signal Transduction (immunology)
• Up-Regulation (immunology)