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However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS\u2010CoV\u20102\u2010infected cells. We adopted a reverse time\u2010order gene coexpression network approach to analyze time\u2010series RNA\u2010sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS\u2010CoV\u20102\u2010activated nuclear factor\u2010\u03baB (NF\u2010\u03baB) and interferon regulatory factor 1\u00a0(IRF1) pathways contributing to viral infection and COVID\u201019 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross\u2010referencing our transcriptomic and epigenomic data sets revealed that coupling NF\u2010\u03baB and IRF1 pathways mediate programmed death ligand\u20101 (PD\u2010L1) immunosuppressive programs. Interestingly, we observed higher PD\u2010L1 expression in Omicron\u2010infected cells than SARS\u2010CoV\u20102 infected cells. Blocking PD\u2010L1 at an early stage of virally\u2010infected AAV\u2010hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS\u2010CoV\u20102\u2010mediated NF\u2010\u03baB and IRF1\u2010PD\u2010L1 axis may represent an alternative strategy to reduce COVID\u201019 severity.<\/jats:p>","DOI":"10.1002\/jmv.28478","type":"journal-article","created":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T08:10:35Z","timestamp":1673079035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Upregulation of PD\u2010L1 by SARS\u2010CoV\u20102 promotes immune evasion"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5413-9775","authenticated-orcid":false,"given":"Hsiang\u2010Chi","family":"Huang","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences Academia Sinica Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Han","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical 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