RNA Structural Domains in Noncoding Regions of the Foot-and-Mouth Disease Virus Genome Trigger Innate Immunity in Porcine Cells and Mice

The induction of type I interferons (alpha/beta interferon [IFN-α/β]) 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-α/β response in porcine kidney cultured cells and newborn mice. These RNAs, generated by in vitro transcription, were able to stimulate IFN-β transcription and induce an antiviral state in SK-6 cells. The induction levels elicited by the different NCR RNAs were compared. Among them, the 3'NCR 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-α/β 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.