{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T07:13:47Z","timestamp":1771485227897,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The recent emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 highlights the need for greater understanding of the immune evasion mechanisms used by Coronavirus (CoVs) to subvert antiviral responses. Previous global outbreaks caused by Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-1 were associated with high mortality rates and limited therapeutic options. Interferon (IFN)-\u03b1 is the body\u2019s natural antiviral agent; but its Janus kinase\/signal transducer and activators of transcription (JAK\/STAT) signalling pathway is often antagonized by viruses, thereby preventing the upregulation of essential, anti-viral IFN Stimulated Genes (ISGs). Notably, therapeutic IFN-\u03b1 has disappointingly weak clinical responses in MERS-CoV and SARS-CoV-1 infected patients, indicating that these CoVs inhibit the IFN-\u03b1 JAK\/STAT pathway. We previously identified that MERS-CoV-non-structural protein(nsp)2 and nsp5 and SARS-CoV-1-nsp14 block the IFN-\u03b1 JAK\/STAT signalling pathway in human epithelial A549 cells; however, the mechanisms behind this inhibition remain unknown. In this study, we explored the factors influencing basal STAT1 and STAT2 phosphorylation and discovered that the expression of MERS-CoV-nsp2 and SARS-CoV-1-nsp14, but not MERS-CoV-nsp5, upregulated IFN-\u03bb1\/3 in A549 cells. Neutralization of IFN-\u03bb1\/3 revealed that this induction was responsible for the observed basal STAT1 and STAT2 phosphorylation, resulting in reduced responsiveness to exogenous IFN-\u03b1. Furthermore, both MERS-CoV-nsp2 and SARS-CoV-1-nsp14 induced the expression of USP18, a negative regulator of the IFN-\u03b1 JAK\/STAT pathway, resulting in reduced responsiveness to exogenous IFN-\u03b1. Silencing USP18 reinstated IFN-\u03b1-mediated STAT1 phosphorylation and ISG induction. Collectively, these findings shed light on the diverse strategies employed by these CoVs to evade type I IFN antiviral responses. While providing evidence for the ineffectiveness of exogenous IFN-\u03b1 treatment during CoV infection, our discoveries also identify these viral proteins as potential targets for therapeutic intervention.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1739662","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T06:42:56Z","timestamp":1771483376000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MERS-CoV and SARS-CoV-1 proteins inhibit the IFN-\u03b1 JAK\/STAT pathway of epithelial cells, via IFN-\u03bb-induced USP18"],"prefix":"10.3389","volume":"17","author":[{"given":"Yamei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nigel 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