Chen Li , Jiabao Shi , Haiwei Wang , Efraín E Rivera-Serrano , Decheng Yang , Guohui Zhou , Chao Sun , Craig E Cameron , Li Yu
J Virol.2020 Oct 7;JVI.01569-20.doi: 10.1128/JVI.01569-20. Online ahead of print.
The low fidelity of foot-and-mouth disease virus (FMDV) RNA-dependent RNA polymerase allows FMDV to exhibit high genetic diversity. Previously, we have shown that the genetic diversity of FMDV plays an important role in virulence in suckling mice. Here, we mutated the amino acid residue Phe257, located in the finger domain of FMDV polymerase and conserved across FMDV serotypes, to a cysteine (F257C) to study the relationship between viral genetic diversity, virulence, and transmissibility in natural hosts. The single amino acid substitution in FMDV polymerase resulted in a high-fidelity virus variant, rF257C, with growth kinetics indistinguishable from wild-type virus in cell culture but displayed smaller plaques and impaired fitness in direct competition assays. Furthermore, we found that the rF257C was attenuated in vivo in both suckling mice and pigs, one of its natural hosts. Importantly, contact-exposure experiments showed that the rF257C virus exhibited reduced transmissibility than wild-type FMDV in the porcine model. This study provides evidence that FMDV genetic diversity is important for viral virulence and transmissibility in susceptible animals. Given that type O FMDV exhibits the highest genetic diversity among all the seven serotypes of FMDV, we propose that the lower polymerase fidelity of the type O FMDV could contribute to its dominance worldwide.IMPORTANCE Among the seven serotypes of FMDV, serotype O FMDV has the broadest distribution worldwide, which could be due to their high virulence and transmissibility induced by the high genetic diversity. In this paper, we generated a single amino acid substitution FMDV variant with a high-fidelity polymerase associated with viral fitness, virulence, and transmissibility in a natural host. The results highlight that maintenance of viral population diversity is essential for interhost viral spread. This study provides evidence that higher genetic diversity of type O FMDV could increase both virulence and transmissibility, thus leading to their dominance in the global epidemic.
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