Foot-and-Mouth Disease Virus Capsid Protein VP1 Antagonizes TPL2-Mediated Activation of the IRF3/IFN-β Signaling Pathway to Facilitate the Virus Replication.

Foot-and-mouth disease (FMD) is a severe, highly contagious viral disease of cloven-hoofed animals. In order to establish an infection, the FMD virus (FMDV) needs to counteract host antiviral responses. Tumor progression locus 2 (TPL2), a mitogen-activated protein kinase, can regulate innate and adaptive immunity; however, its exact mechanisms underlying TPL2-mediated regulation of the pathogenesis of FMDV infection remain unknown. In this study, we confirmed that TPL2 could inhibit FMDV replication and . The virus replication increased in -deficient suckling mice in association with reduced expression of interferon-stimulated genes interferon-α (IFN-α) and myxovirus resistance (MX2) and significantly reduced expression of C-X-C motif chemokine ligand 10 (CXCL10), interferon regulatory factor 3 (IRF3), and IRF7, while the phosphorylation of IRF3 was not detected. Moreover, the interactions between TPL2 and VP1 were also confirmed. The overexpression of TPL2 promoted IRF3-mediated dose-dependent activation of the IFN-β signaling pathway in association with interactions between IRF3 and TPL2. VP1 also inhibited phosphorylation of TPL2 at Thr290, while Thr290 resulted as the key functional site associated with the TPL2-mediated antiviral response. Taken together, this study indicated that FMDV capsid protein VP1 antagonizes TPL2-mediated activation of the IRF3/IFN-β signaling pathway for immune escape and facilitated virus replication.