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

Abstract

The interferon pathway represents a key antiviral defense mechanism and is being considered as a therapeutic target in COVID-19. Both, substitution of interferon and blocking interferon signaling through JAK STAT inhibition to limit cytokine storms have been proposed. However, little is known so far about possible abnormalities in STAT signaling in immune cells during SARS-CoV-2 infection. In the current study, we investigated downstream targets of interferon signaling, including STAT1, 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 an 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. Most interestingly, Siglec-1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe COVID-19 cases compared to mild cases. Contrary to the baseline whole protein 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. The data suggest impaired STAT1 transcriptional upregulation among severely infected patients which may represent a potential predictive biomarker and may allow stratification of patients for certain interferon-pathway targeted treatments.

Plasmablast‐like Phenotype Among Antigen‐Experienced CXCR5–CD19low B Cells in Systemic Lupus Erythematosus

“…Recently, investigators found that alterations in the immune response of individuals with severe SARS-CoV-2 infection are similar to those associated with autoimmunity, leading to new insights into immunopathogenesis. For example, COVID-19 and SLE both involve increased induction of extrafollicular CD19 high CD11c high B cells (26,43), as well as changes in the interferon response (44,45) and its regulation (46). Associations between COVID-19 and new-onset autoimmune rheumatic diseases, including SLE, were recently described (47,48).…”

Myeloid CD169/Siglec1: An immunoregulatory biomarker in viral disease

“…Although not shown in respiratory viral infection, several studies, found the sialic acid containing monosialodihexosylganglioside (GM3) to be another physiological ligand of CD169 (54)(55)(56)(57) In vivo analyses revealed a direct and clear upregulation of the receptor upon IFN-I (α/β/ω) stimulation within the physiological ranges of viral infection (58). In addition, significant changes in pSTAT1 and pSTAT2, pathways that are crucially involved in antiviral activity, have been detected (58,59). Of note, CD169+ macrophages have been found to be one of the main IFN-1 producers upon virus infection, themselves, making a selfenforcing process of IFN-mediated antiviral activity conceivable (27).…”

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.…”