Decheng Yang , Chao Sun , Rongyuan Gao , Haiwei Wang , Wenming Liu , Kewei Yu , Guohui Zhou , Bo Zhao , Li Yu
J Virol.2020 Jun 3;JVI.00990-20.doi: 10.1128/JVI.00990-20.Online ahead of print.
Foot-and-mouth disease (FMD), which is caused by FMD virus (FMDV), remains a major plague among cloven-hoofed animals worldwide, and its outbreak often has disastrous socio-economic consequences. A live-attenuated FMDV vaccine will greatly facilitate the global control and eradication of FMD, but a safe and effective attenuated FMDV vaccine has not yet been successfully developed. Here, we found that the internal ribosome entry site (IRES) element in the viral genome is a critical virulence determinant of FMDV, and a nucleotide substitution of cytosine (C) for guanine (G) at position 351 of the IRES endows FMDV with temperature-sensitive and attenuation (ts&att) phenotypes. Further, we demonstrated that the C351G mutation of IRES causes a temperature-dependent translation defect by impairing its binding to cellular pyrimidine tract-binding protein (PTB), resulting in the ts&att phenotypes of FMDV. Natural hosts inoculated with viruses carrying the IRES C351G mutation showed no clinical signs, viremia, virus excretion, or viral transmission but still produced a potent neutralizing-antibody response that provided complete protection. Importantly, the IRES C351G mutation is a universal determinant of the ts&att phenotypes of different FMDV strains, and the C351G mutant was incapable of reversion to virulence during in vitro and in vivo passages. Collectively, our findings suggested that manipulation of the IRES, especially its C351G mutation, may serve as a feasible strategy to develop live-attenuated FMDV vaccines.IMPORTANCE The World Organization for Animal Health has called for global control and eradication of FMD, the most economically and socially devastating disease affecting animal husbandry worldwide. Live-attenuated vaccines are considered the most effective strategy for prevention, control and eradication of infectious diseases due to their capacity to induce potent and long-lasting protective immunity. However, efforts to develop FMDV live-attenuated vaccines have achieved only limited success. Here, by structure-function study of the FMDV IRES we find that the C351 mutation of the IRES confers FMDV with an ideal temperature-sensitive attenuation phenotype by decreasing its interaction with cellular PTB to cause IRES-mediated temperature-dependent translation defects. The temperature-sensitive attenuated strains generated by manipulation of the IRES address the challenges of FMDV attenuation differences among various livestock species and immunogenicity maintenance encountered previously, and this strategy can be applied to other viruses with an IRES to rationally design and develop live-attenuated vaccines.
Copyright © 2020 American Society for Microbiology.