Host-Specific Interplay between Foot-and-Mouth Disease Virus 3D Polymerase and the Type-I Interferon Pathway

Foot-and-mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals. One of the issues related to this disease is the persistence of its causative agent, foot-and-mouth disease virus (FMDV). While the mechanisms of FMDV persistence remain unclear, there are clues that it may be related to protein-protein interactions (PPI) between viral proteins and cellular proteins involved in the interferon (IFN) response. Since FMDV persistence has been described in cattle, sheep and goats but not in swine, we screened PPI involving FMDV proteins and sixteen major type-I IFN pathway proteins from these four species by nanoluciferase-2-hybrid complementation assay, in order to identify new PPI and determine their host specificity. As the results concerning the 3D^pol were the most interesting in view of the limited data concerning its role in immune escape, we decided to focus particularly on this protein. The identified PPI were confirmed by GST pull-down. We identified PPI between 3D^pol and seven IFN pathway proteins, namely, IKKα, IKKε, IRF3, IRF7, NEMO, MDA5 and MAVS. These PPI are conserved among the four studied species, with the exception of the one between 3D^pol and MAVS, which was only found with the swine protein. We also showed, using luciferase reporter assays, that 3D^pol could inhibit the induction phase of the IFN pathway. These results demonstrate, for the first time, a putative role for 3D^pol in FMDV innate immune escape.