Attenuation of Foot-and-Mouth Disease Virus by Engineered Viral Polymerase Fidelity

Journal of Virology
Devendra K RaiElizabeth Rieder

Abstract

Foot-and-mouth disease virus (FMDV) RNA-dependent RNA polymerase (RdRp) (3Dpol) catalyzes viral RNA synthesis. Its characteristic low fidelity and absence of proofreading activity allow FMDV to rapidly mutate and adapt to dynamic environments. In this study, we used the structure of FMDV 3Dpolin combination with previously reported results from similar picornaviral polymerases to design point mutations that would alter replication fidelity. In particular, we targeted Trp237 within conserved polymerase motif A because of the low reversion potential inherent in the single UGG codon. Using biochemical and genetic tools, we show that the replacement of tryptophan 237 with phenylalanine imparts higher fidelity, but replacements with isoleucine and leucine resulted in lower-fidelity phenotypes. Viruses containing these W237 substitutions showin vitrogrowth kinetics and plaque morphologies similar to those of the wild-type (WT) A24Cruzeiro strain in BHK cells, and both high- and low-fidelity variants retained fitness during coinfection with the wild-type virus. The higher-fidelity W237F (W237FHF) mutant virus was more resistant to the mutagenic nucleoside analogs ribavirin and 5-fluorouracil than the WT virus, whereas the lower-fideli...Continue Reading

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Citations

Aug 3, 2018·Journal of Virology·Ignacio de la HigueraEsteban Domingo
Mar 29, 2019·PLoS Genetics·Xumin OuQiuwei Pan
Aug 30, 2019·Journal of Virology·Tadasuke NaitoMineki Saito
Aug 4, 2018·MSystems·Matthew L PaffClaus O Wilke
Sep 5, 2019·Frontiers in Cellular and Infection Microbiology·Javier Orlando Cifuente, Gonzalo Moratorio
Mar 16, 2018·Microbiology and Molecular Biology Reviews : MMBR·Vadim I Agol, Anatoly P Gmyl
Feb 9, 2021·Frontiers in Microbiology·Fayna Diaz-San SegundoTeresa de Los Santos

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