tetano
Editor, Senior Moderator
Front Immunol
. 2023 May 16;14:1166574.
doi: 10.3389/fimmu.2023.1166574. eCollection 2023. Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity
Rachel MacCann[SUP] 1 2 3 [/SUP], Alejandro Abner Garcia Leon[SUP] 3 [/SUP], Gabriel Gonzalez[SUP] 3 4 5 [/SUP], Michael J Carr[SUP] 1 4 6 [/SUP], Eoin R Feeney[SUP] 1 2 [/SUP], Obada Yousif[SUP] 7 [/SUP], Aoife G Cotter[SUP] 3 8 [/SUP], Eoghan de Barra[SUP] 9 10 [/SUP], Corinna Sadlier[SUP] 11 [/SUP], Peter Doran[SUP] 1 [/SUP], Patrick W Mallon[SUP] 1 2 3 [/SUP]
Affiliations
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: COVID-19; SARS-CoV-2; gene expression; interferon; mast cells; plasma biomarkers.
. 2023 May 16;14:1166574.
doi: 10.3389/fimmu.2023.1166574. eCollection 2023. Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity
Rachel MacCann[SUP] 1 2 3 [/SUP], Alejandro Abner Garcia Leon[SUP] 3 [/SUP], Gabriel Gonzalez[SUP] 3 4 5 [/SUP], Michael J Carr[SUP] 1 4 6 [/SUP], Eoin R Feeney[SUP] 1 2 [/SUP], Obada Yousif[SUP] 7 [/SUP], Aoife G Cotter[SUP] 3 8 [/SUP], Eoghan de Barra[SUP] 9 10 [/SUP], Corinna Sadlier[SUP] 11 [/SUP], Peter Doran[SUP] 1 [/SUP], Patrick W Mallon[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 37261339
- PMCID: PMC10229044
- DOI: 10.3389/fimmu.2023.1166574
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: COVID-19; SARS-CoV-2; gene expression; interferon; mast cells; plasma biomarkers.