T135I substitution in the nonstructural protein 2C enhances foot-and-mouth disease virus replication

Yuan, Tiangang; Wang, Haiwei; Li, Chen; Yang, Decheng; Zhou, Guohui; Yu, Li

doi:10.1007/s11262-017-1480-9

Cited by 8 publications

(4 citation statements)

References 36 publications

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“…Identification of the FMDV 2C Knob loop provides a mechanistic explanation for a previous study showing that the mutation FMDV 2C T135I enhances viral replication (Yuan et al, 2017). We reveal that T135 is on the Knob loop, and that the infectious clone harboring 2C T135A failed in FMDV rescue (Table S2).…”

Section: Discussionsupporting

confidence: 66%

An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein

Zhang¹,

Yang²,

Wojdyla³

et al. 2022

Cell Reports

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Section: Discussionsupporting

confidence: 66%

An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein

Zhang¹,

Yang²,

Wojdyla³

et al. 2022

Cell Reports

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“…substitution (T135I) in nonstructural protein 2C, which is required for adaptation of the FMDV strain to BHK-21 cells as reported previously (31). The C4837T mutation also emerged in parallel passages of FMDV(WT).…”

Section: Replacement Of Fmdv Ires Domain 4 With Brbv Ires Domain 4 Resupporting

confidence: 56%

A Temperature-Dependent Translation Defect Caused by Internal Ribosome Entry Site Mutation Attenuates Foot-and-Mouth Disease Virus: Implications for Rational Vaccine Design

Yang

Sun

Gao

et al. 2020

J Virol

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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.

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“…Rehabilitation of fitness impairments caused by deletions in a nonstructural protein may sometimes be accomplished by the acquisition of compensatory mutations in other nonstructural proteins, as exemplified by the restoration of the replicative efficiency of an FMDV mutant lacking a significant part of its 3A protein by a point mutation in 2C (392).…”

Section: Rehabilitation After Large Indels and Replacementsmentioning

confidence: 99%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

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T135I substitution in the nonstructural protein 2C enhances foot-and-mouth disease virus replication

Cited by 8 publications

References 36 publications

An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein

An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein

A Temperature-Dependent Translation Defect Caused by Internal Ribosome Entry Site Mutation Attenuates Foot-and-Mouth Disease Virus: Implications for Rational Vaccine Design

Emergency Services of Viral RNAs: Repair and Remodeling

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