Foot-and-mouth disease virus VP1 target the MAVS to inhibit type-I interferon signaling and VP1 E83K mutation results in virus attenuation

VP1, a pivotal capsid protein encoded by the foot-and-mouth disease virus (FMDV), plays an important role in receptor-mediated attachment and humoral immune responses. Previous studies show that amino acid changes in the VP1 protein of cell culture-adapted strains of FMDV alter the properties of the virus. In addition, FMDV VP1 modulates host IFN signal transduction. Here, we examined the ability of cell culture-adapted FMDV VP1(83K) and wild-type FMDV VP1(83E) to evade host immunity by blocking mitochondrial antiviral signaling protein (MAVS)/TNF Receptor Associated Factor 3 (TRAF3) mediated cellular innate responses. Wild-type FMDV VP1(83E) interacted specifically with C-terminal TRAF3-binding site within MAVS and this interaction inhibited binding of TRAF3 to MAVS, thereby suppressing interferon-mediated responses. This was not observed for cell culture-adapted FMDV VP1(83K). Finally, chimeric FMDV harboring VP1(83K) showed very low pathogenicity in pigs. Collectively, these data highlight a critical role of VP1 with respect to suppression of type-I IFN pathway and attenuation of FMDV by the E83K mutation in VP1.
Author summary Foot-and-Mouth disease (FMD), a highly contagious viral disease of cloven-hoofed animals, causes huge economic losses. To generate a FMD vaccine, cell culture-adapted strains of FMDV that show improved growth properties and allow repeated passage are needed. Generally, adaptation of field-isolated FMDV is accompanied by changes in viral properties, including amino acid mutations. A VP1 E83K mutation in cell culture-adapted FMDV was identified previously; here, we examined the impact of VP1 E83K on virus pathogenicity and type-I IFN pathway. Cell culture-adapted FMDV O1 Manisa, and highly virulent strain of O/Andong/SKR/2010, acquired the E83K mutation in the VP1 protein, which attenuated the virus via disposing VP1 mediate negative regulation ability of host cellular IFN responses. The data suggest a rational approach to viral propagation in cell culture and virus attenuation, which could be utilized for future development of FMDV vaccines.