Host innate immune response is the first-line defence triggered by type I interferon. Type I interferon production is activated through the detection of replicating viral RNA by cytoplasmic RNA sensors RIG-I and MDA5. Oligomerization of adaptor protein MAVS is induced by the activation of RNA sensor, leading to the formation of TRAF3-TANK-TBK1/IKKϵ complex, which phosphorylates transcription factor IRF3 and drives type I IFN transcription [49]. Highly pathogenic HCoVs often encode viral proteins with a higher capability to antagonize RNA-induced type I interferon production through perturbation of RNA sensing. For one example, double-stranded RNA (dsRNA)-binding domain of MERS-CoV ORF4a is responsible for the suppression of Sendai virus- or poly (I:C)-induced type I interferon production [60]. The gain of dsRNA-binding ability is observed in bat CoV HKU5 but not HKU4, suggesting that the functional gain of MERS-CoV ORF4a and HKU5 ORF4a might be acquired at a later stage in evolution [60]. For another example, only M proteins from highly pathogenic CoVs, SARS-CoV and MERS-CoV, were reported to potently suppress type I interferon production [61,62], suggesting that the loss of this activity might have taken place during viral evolution, leading to attenuation.