Foot-and-mouth disease virus 5’-terminal S fragment is required for replication and modulation of the innate immune response in host cells

The S fragment of the FMDV 5’ UTR is predicted to fold into a long stem-loop structure and it has been implicated in virus-host protein interactions. In this study, we report the minimal S fragment sequence required for virus viability and show a direct correlation between the extent of the S fragment deletion mutations and attenuated phenotypes. Furthermore, we provide novel insight into the role of the S fragment in modulating the host innate immune response. Importantly, in an FMDV mouse model system, all animals survive the inoculation with the live A₂₄ FMDV-S₄ mutant, containing a 164 nucleotide deletion in the upper S fragment loop, at a dose 1000 higher than the one causing lethality by parental A₂₄ FMDV, indicating that the A₂₄ FMDV-S₄ virus is highly attenuated in vivo. Additionally, mice exposed to high doses of live A₂₄ FMDV-S₄ virus are fully protected when challenged with parental A₂₄ FMDV virus.