{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:58:44Z","timestamp":1790686724166,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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>Middle East respiratory syndrome coronavirus (MERS-CoV) is a merbecovirus associated with recurrent zoonotic spillover and severe lower-respiratory disease. Research has focused largely on DPP4-mediated entry, spike structure, replicase biology, neutralizing antibodies, and vaccines. However, the 3\u2032-encoded accessory proteins are increasingly recognized as context-dependent modulators of viral fitness and pathogenesis. ORF4a binds double-stranded RNA (dsRNA) and suppresses MDA5- and PKR-dependent antiviral responses; ORF4b antagonizes OAS\u2013RNase L and NF-\u03baB signaling and contributes to inflammatory pathology in defined infection models; ORF5 modulates interferon and inflammatory responses in a genetic-background-dependent manner; and ORF8b interferes with MDA5- and HSP70\u2013IKK\u03f5-dependent signaling, although its pathogenesis phenotype varies by experimental system and viral background. ORF3 shows HUWE1-regulated pro-apoptotic activity in ectopic-expression systems, but its role during authentic MERS-CoV infection remains unresolved. Our review organizes these findings by evidence type, pathway position, cell or tissue context, sampling time, and genetic-interaction evidence. This framework separates demonstrated mechanisms from inferred biological consequences and identifies the validation required before accessory-ORF biology can inform host-range assessment, therapeutic development, sequence surveillance, or rational attenuation.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1963823","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:13:54Z","timestamp":1790684034000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MERS-CoV accessory ORF proteins in innate immune evasion: an evidence-graded functional framework"],"prefix":"10.3389","volume":"17","author":[{"given":"Chunhua","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Central Laboratory, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Xiangyang Hospital of Traditional Chinese Medicine [Xiangyang Institute of Traditional Chinese Medicine]","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Central Laboratory, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science","place":["Xiangyang, Hubei, China"]},{"name":"School of Clinical Medicine, Hubei University of Arts and Science","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Hubei University of Arts and Science","place":["Xiangyang, Hubei, 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