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.

Discovering hub genes involved in the pathophysiological impact of COVID-19 on diabetes kidney disease by differential gene expression and interactome analysis

“…Overall, our transcriptomics results suggest that the shared DEGs between DKD and SARS-CoV-2 infection represent a transcriptional reprogramming in the host response, undergoing a remarkable upregulation of key genes such as the above described, which is in accordance with previous recent studies [75,76]. For instance, the activation of antiviral biomolecule pathways such as JAK1/STAT1 and ISG15/MX1 , respectively.…”

“…Notably, STAT1 -signaling pathway is associated with renal inflammation and renal injury [89]. Also, it has been reported an upregulation of this biomolecule in mildly to severely affected COVID-19 patients [76].…”

Comparison of cell type annotation algorithms for revealing immune response of COVID-19

“…STAT1 acts as a downstream effector of interferon signaling. Its upregulation was reported to be positively correlated with the severity of COVID-19 patients (Rincon-Arevalo et al, 2022). The differential expression of STAT1 in pDCs observed in our analysis aligned well with its function to amplify IFN-mediated signals.…”

Next-generation proteomics of serum extracellular vesicles combined with single-cell RNA sequencing identifies MACROH2A1 associated with refractory COVID-19

“…Regarding the STAT pathway, another important regulatory relationship, it is particularly important that the JAK/STAT (Janus kinase/ Signal Transducer and Activator of Transcription) pathway regulates inflammatory cytokine signaling associated with SARS-CoV-2 infection. In monocytes, STAT1, STAT2 and IFN regulatory factors are activated [ 59 , 60 ]. The above hypothesized mechanisms provide us with a new perspective on MACROH2A1-mediated severe COVID-19 pathogenesis, and further in vitro and in vivo studies are warranted.…”