Upregulation of PD-L1 by SARS-CoV-2 promotes immune evasion

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-& kappa;B (NF-& kappa;B) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-& kappa;B and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-& kappa;B and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

Automated summary

Patients with severe COVID-19 often experience lymphopenia, and this study aims to understand how SARS-CoV-2 induces this condition. The researchers analyzed the transcriptomic and epigenomic changes in infected cells and found that the NF-κB and IRF1-PD-L1 pathways play a role in viral infection and COVID-19 severity. They also observed higher expression of PD-L1 in Omicron-infected cells compared to SARS-CoV-2-infected cells. Blocking PD-L1 in virally-infected mice showed promising results in recovering lymphocyte counts and reducing inflammatory cytokine levels. Targeting the NF-κB and IRF1-PD-L1 axis could be an alternative strategy to mitigate the severity of COVID-19.