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. Anomalous upregulation of STAT1 and IRF9 (key components of IFN signaling) in B and T cells and monocytes from patients with severe COVID‐19, with absence of pSTAT1 upregulation upon IFN restimulation. Mild COVID‐19 group had strong STAT1 and IRF9 upregulation.
【저자키워드】 COVID‐19, type I interferon, Stat1, IRF9, pSTAT1, 【초록키워드】 Stratification, Monocytes, Severe infection, Cytokine storm, Biomarker, Transcription, interferon, IFN signaling, flow cytometry, monocyte, COVID‐19, T cell, Patient, Phosphorylation, Mild, IFN, PBMC, interferon signaling, target, expression, IRF1, CD169, JAK/STAT, Signaling, STAT, Immune cell, interferon pathway, therapeutic target, Predictive, STAT2, mild cases, Severe case, plasmablast, upregulation, SARS‐CoV‐2 infection, component, lower expression, abnormality, element, Transcriptional upregulation, downstream, limit, JAK/STAT signaling, IFN‐γ, stimulated, investigated, absence, correlated, induce, antiviral defense mechanism, baseline, CD14+ monocyte, ISRE, severely infected patient, 【제목키워드】 COVID‐19, Phosphorylation, expression, increase in, Altered,