Journal Article

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

Eoghan de Barra, Aoife G. Cotter, Michael J. Carr, Patrick W. Mallon, Gabriel Gonzalez, Rachel MacCann, Alejandro Abner Garcia Leon, Eoin R. Feeney, Corinna Sadlier, Peter Doran, Obada Yousif

2023

Overview

Dysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease. We analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-β), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays. We identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19. This study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Asymptomatic / Biomarkers / Cell activation / Cell Line / Clinical outcomes / Cohort analysis / Coronaviruses / COVID-19 / Cytokines / Gene expression / Humans / Immune response / Immune system / Immunologic diseases. Allergy / Immunology / Infectious diseases / Inflammation / interferon / Interferon regulatory factor 4 / Interferon regulatory factor 7 / Interferon Type I / Leukocytes, Mononuclear / Mast Cells / Mortality / OX40 Ligand / Peripheral blood mononuclear cells / Plasma / plasma biomarkers / Plasma levels / Quality control / RC581-607 / Research ethics / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Signal transduction / Stat1 protein / Stat2 protein / Tumor necrosis factor-TNF / Viral infections / β-Interferon / γ-Interferon