MERS-CoV accessory ORF proteins in innate immune evasion: an evidence-graded functional framework

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.