tetano
Editor, Senior Moderator
Front Immunol
. 2026 Sep 29:17:1963823.
doi: 10.3389/fimmu.2026.1963823. eCollection 2026.
Chunhua Wang # 1 , Xuhang Li # 2 , Yi Jiang # 1 3 , Jinhui Yang 3 , Minghui Yang 4 , Yang Yang 5 , Mengjun Tang 1 , Wenjie Tan 6 , Ji Zhang 1
Affiliations Expand
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'-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-RNase L and NF-κB 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-IKKϵ-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.
Keywords: MERS-CoV; ORF3; ORF4a; ORF4b; ORF5; ORF8b; accessory protein; innate immune evasion.
. 2026 Sep 29:17:1963823.
doi: 10.3389/fimmu.2026.1963823. eCollection 2026.
MERS-CoV accessory ORF proteins in innate immune evasion: an evidence-graded functional framework
Chunhua Wang # 1 , Xuhang Li # 2 , Yi Jiang # 1 3 , Jinhui Yang 3 , Minghui Yang 4 , Yang Yang 5 , Mengjun Tang 1 , Wenjie Tan 6 , Ji Zhang 1
Affiliations Expand
- PMID: 42872108
- PMCID: PMC13659741
- DOI: 10.3389/fimmu.2026.1963823
Abstract
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'-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-RNase L and NF-κB 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-IKKϵ-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.
Keywords: MERS-CoV; ORF3; ORF4a; ORF4b; ORF5; ORF8b; accessory protein; innate immune evasion.