-Foot-and-mouth disease virus (FMDV) was the first animal virus identified. Since then, FMDV has become a model system in animal virology and a considerable amount of information on its structure, biology and vaccinology has been obtained. However, the disease that this virus produces (FMD) still constitutes one of the main animal health concerns. In this review, we have attempted to summarise the state of the knowledge in different basic and applied areas of FMDV research, with emphasis on those aspects relevant to the control of the disease. FMDV / structure / immunity / vaccine / variability / diagnosisRésumé -Le virus de la fièvre aphteuse : un virus connu de longue date, qui demeure une menace. Le virus de la fièvre aphteuse a été le premier virus animal identifié. Depuis lors, il est devenu un système modèle en virologie animale, et une quantité importante d'informations sur sa structure, sa biologie et sa vaccinologie a été obtenue. Cependant la maladie provoquée par ce virus constitue encore une inquiétude majeure en santé animale. Dans cette revue, nous avons tenté de résumer l'état des connaissances dans différents domaines de recherche, à la fois fondamentaux et appliqués, sur le virus de la fièvre aphteuse, en mettant l'accent sur les aspects relatifs au contrôle de la maladie. virus de la fièvre aphteuse / immunité / vaccin / variabilité / diagnostic

The untranslated regions (UTRs) of the foot-and-mouth disease virus (FMDV) genome contain multiple functional elements. In the 59 UTR, the internal ribosome entry site (IRES) element governs cap-independent translation initiation, whereas the S region is presumably involved in RNA replication. The 39 UTR, composed of two stem-loops and a poly(A) tract, is required for viral infectivity and stimulates IRES activity. Here, it was found that the 39 end established two distinct strand-specific, long-range RNA-RNA interactions, one with the S region and another with the IRES element. These interactions were not observed with the 39 UTR of a different picornavirus. Several results indicated that different 39 UTR motifs participated in IRES or S region interactions. Firstly, a high-order structure adopted by both the entire IRES and the 39 UTR was essential for RNA interaction. In contrast, the S region interacted with each of the stem-loops. Secondly, S-39 UTR interaction but not IRES-39 UTR interaction was dependent on a poly(A)-dependent conformation. However, no other complexes were observed in mixtures containing the three transcripts, suggesting that these regions did not interact simultaneously with the 39 UTR probe. Cellular proteins have been found to bind the S region and one of these also binds to the 39 UTR in a competitive manner. Our data suggest that 59-39-end bridging through both direct RNA-RNA contacts and RNA-protein interactions may play an essential role in the FMDV replication cycle.

The 3' end region of foot-and-mouth disease virus (FMDV) consists of two distinct elements, a 90 nt untranslated region (3'-NCR) and a poly(A) tract. Removal of either the poly(A) tract or both the 3'-NCR and the poly(A) tract abrogated infectivity in susceptible cells in the context of a full-length cDNA clone. We have addressed the question of whether the impairment of RNA infectivity is related to defects at the translation level using a double approach. First, compared to the full-length viral RNA, removal of the 3' sequences reduced the efficiency of translation in vitro. Secondly, a stimulatory effect of the 3' end sequences on IRES-dependent translation was found in vivo using bicistronic constructs. RNAs carrying the FMDV 3' end sequences linked to the second cistron showed a significant stimulation of IRES-dependent translation, whereas cap-dependent translation was not affected. Remarkably, IRES-dependent stimulation exerted by the poly(A) tract or the 3'-NCR seems to be the result of two separate events, as the 3'-NCR alone enhanced IRES activity on its own. Under conditions of FMDV Lb protease-induced translation shut-off, the stimulation of IRES activity reached values above 6-fold in living cells. A northern blot analysis indicated that IRES stimulation was not the consequence of a change in the stability of the bicistronic RNA produced in transfected cells. Analysis of the RNA-binding proteins interacting with a mixture of 3' end and IRES probes showed an additive pattern. Altogether, our results strongly suggest that individual signals in the viral 3' end ensure stimulation of FMDV translation.

The induction of type I interferons (alpha/beta interferon [IFN-␣/␤]) in response to viral infection is a crucial step leading to the antiviral state in the host. Viruses produce double-stranded RNA (dsDNA) during their replication cycle that is sensed as nonself by host cells through different receptors. A signaling cascade then is activated to block viral replication and spread. Foot-and-mouth disease virus (FMDV) is a picornavirus that is highly sensitive to IFN, and it causes one of the world's most important animal diseases. In this study, we showed the ability of structural domains predicted to enclose stable dsRNA regions in the 5-and 3-noncoding regions (NCRs) of the FMDV genome to trigger an IFN-␣/␤ response in porcine kidney cultured cells and newborn mice. These RNAs, generated by in vitro transcription, were able to stimulate IFN-␤ transcription and induce an antiviral state in SK-6 cells. The induction levels elicited by the different NCR RNAs were compared. Among them, the 3NCR was identified as a potent IFN activator, and the features in this region involved in signaling have been analyzed. To address whether the FMDV NCR transcripts were able to trigger the innate immune response in vivo, Swiss suckling mice were inoculated intraperitoneally with the RNAs. All transcripts induced the innate response in transfected animals, measured as IFN-␣/␤ protein levels, antiviral activity in sera, and reduced susceptibility to FMDV infection. Our work provides new insight into innate responses against FMDV and identifies these small noninfectious RNA molecules as potential adjuvants for vaccine improvement and antiviral strategies against picornaviruses.The innate immune response is a first line of defense against invading pathogens, and it depends on several sensors and signaling pathways. The detection of viral products as pathogen-associated molecular patterns (PAMPs) initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I IFNs (IFN-␣ and IFN-␤) that have antiviral, antiproliferative, and immunomodulatory functions. PAMPs presented during viral infections include singlestranded RNA (ssRNA) and double-stranded RNA (dsRNA). dsRNA is generated in infected cells as genomic fragments, replicative intermediate, or by stem-loop structures and is recognized by viral sensors. Toll-like receptors (TLRs), expressed on the surface and endosomal compartments of some cell types, and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), ubiquitous cytosolic RNA helicases, are the two major systems for virus detection (5, 21, 49, 51, 52). The RLRs RIG-I and melanoma differentiation antigen 5 (MDA-5) play critical roles in triggering immune defenses against RNA virus infection (22). Recently, class A scavenger receptors (SR-As) have been shown to recognize extracellular dsRNA and mediate its entry and delivery to intracellular sensors (12).Foot-and-mouth disease virus (FMDV) is a member of the Picornaviridae family and the causative agent of an acute vesicular disea...