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

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• The interferon pathway is crucial for antiviral defense and a potential therapeutic target in COVID-19.
• Understanding STAT signaling abnormalities in immune cells during SARS-CoV-2 infection is critical.

Purpose of the Study:

• To investigate downstream targets of interferon signaling, including STAT1, STAT2, and IRFs, in immune cells of COVID-19 patients.
• To analyze STAT signaling dysregulation in relation to disease severity.

Main Methods:

• Flow cytometry was used to analyze STAT1, STAT2, pSTAT1/2, IRF1, IRF7, and IRF9 expression in immune cells from 30 COVID-19 patients (17 mild, 13 severe).
• Interferon (IFN)-signature was assessed by Siglec-1 expression on monocytes.
• Peripheral blood mononuclear cells (PBMCs) from severe cases were stimulated with IFN-α and IFN-γ to assess signaling persistence.

Main Results:

• STAT1 and IRF9 were upregulated in both mild and severe COVID-19 cases, correlating with the IFN-signature.
• Severe COVID-19 cases exhibited lower Siglec-1 and STAT1 expression on CD14+ monocytes and plasmablasts compared to mild cases.
• Despite baseline STAT1 upregulation, enhanced STAT1 phosphorylation in severe cases indicated dysbalanced JAK/STAT signaling, failing to induce interferon-stimulated response elements (ISRE).
• This signaling abnormality persisted even after IFN-α and IFN-γ stimulation in severe COVID-19 patients.

Conclusions:

• Impaired STAT1 transcriptional upregulation in severe COVID-19 suggests a dysregulated interferon response.
• These findings identify potential predictive biomarkers for patient stratification in interferon-targeted COVID-19 therapies.