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Foot-and-mouth disease (FMD) is a highly contagious disease caused by FMD virus (FMDV) in cloven-hoofed animals. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are representative receptors in the cytoplasm for the detection of viral RNA and trigger antiviral responses, leading to the production of type I interferon. Although MDA5 is a crucial receptor for sensing picornavirus RNA, the interplay between MDA5 and FMDV is relatively unknown compared to the interplay between RIG-I and FMDV. Here, we observed that the FMDV infection inhibits MDA5 protein expression. Of the non-structural proteins, the Lb and 3C proteinases (Lb pro and 3C pro ) were identified to be primarily responsible for this inhibition. However, the inhibition by 3C pro was independent of proteasome, lysosome and caspase-dependent pathway and was by 3C protease activity. A direct interaction between 3C pro and MDA5 protein was observed. In conclusion, this is the first report that 3C pro inhibits MDA5 protein expression as a mechanism to evade the innate immune response during FMDV infection. These results elucidate the pathogenesis of FMDV and provide fundamental insights for the development of a novel vaccine or therapeutic agent.

Foot-and-Mouth Disease Virus Evades Innate Immune Response by 3C-Targeting of MDA5