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Foot-and-Mouth Disease (FMD) is a highly contagious viral animal disease affecting wild and domestic artiodactyls. More than five hundred years after it was first described, FMD remains a major threat to animal health. Following FMDV (Foot-and-Mouth Disease Virus) infection, more than 50% of ruminants become persistently infected. Interestingly, no signs of persistence have been identified in swine. Although decades have been spent studying the persistence of FMDV, the mechanisms underlying its establishment, maintenance and resolution remain to be elucidated. However, some insights have already been uncovered. A FMDV-host co-evolution has been demonstrated, as well as the immunomodulatory effect of the virus. Using a model of primary bovine cells derived from the dorsal soft palate, the main site of primary replication and persistence of the virus in vivo, it has been possible to characterise the transcriptional responses of the host during FMDV infection. It was shown that acute infection is characterised by the induction of a significant antiviral response, while persistent infection is associated with a long-lasting but diminished innate immune response that is ineffective in eliminating the virus. Like many viruses, FMDV has developed strategies for escaping the innate response, mainly by targeting type I interferons (IFN). Taken together, these data suggest that a balance is established between the virus presence and the host's response, through the establishment of protein-protein interactions during persistent infection.Since the antagonisms described between FMDV proteins and type I IFN pathway proteins have been reported in cell systems from different species, often with little relevance with regard to the virus pathophysiology, the main purpose of this thesis project was to identify interactions between FMDV and the type I IFN pathway and to determine their possible host specificity. The interactions established between FMDV serotype O proteins and sixteen type I IFN pathway proteins involved in more than 75% of virus-host interactions, from three species in which the virus persists (Bos taurus, Ovis aries and Capra hircus) and one species in which it does not (Sus scrofa), were identified using an “interferactomic” approach. Seven new viral antagonisms involving the 3D polymerase, whose role in subverting the antiviral response is poorly documented, were identified. Six of these were identified as being conserved within the four species studied, while the interaction between the 3D polymerase and MAVS was only observed for the porcine form of this cellular protein.This thesis work also enabled the development of primary porcine and ovine cell models adapted to the study of FMDV by analogy with that developed with primary bovine cells. The short- and long-term infection of these models by FMDV was characterised and compared with the in vivo observations presented in the literature. Ultimately, these models could provide an alternative to the cell lines currently used, which are not derived from tissues of interest. These models are also tools for studying host responses to FMDV infection and are intended to validate the protein interactions identified during this thesis in an infectious context. To this end, the reactivity of antibodies targeting type I IFN pathway proteins was tested against proteins from the four target species. The two references that were validated were then used to highlight the interactions between the IKKε and NEMO proteins and the FMDV 3D polymerase.