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.

FMDV 5'UTR的S片段预计会折叠成一个长的茎-环结构，并且与病毒-宿主蛋白相互作用有关。在这项研究中，我们报告了病毒生存能力所需的最小S片段序列，并显示了S片段缺失突变的程度与减毒表型之间的直接相关性。此外，我们提供了S片段在调节宿主先天免疫应答中的作用的新颖见解。重要的是，在FMDV小鼠模型系统中，所有动物都存活了活的A ₂₄ FMDV-S ₄突变体，该突变体在上S片段环中含有164个核苷酸的缺失，其剂量比引起亲代A致死的剂量高1000倍。₂₄ FMDV，表示A ₂₄FMDV-S ₄病毒在体内高度减毒。另外，当暴露于亲本A ₂₄ FMDV病毒时，暴露于高剂量活A ₂₄ FMDV-S ₄病毒的小鼠受到完全保护。