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Characterization of a chimeric foot-and-mouth disease virus bearing a bovine rhinitis B virus leader proteinase
- Uddowola, Sabena, Pacheco, Juan M., Larson, Christopher, Bishop, Elizabeth, Rodriguez, Luis L., Rai, Devendra K., Arzt, Jonathan, Rieder, Elizabeth
- Virology 2013 v.447 no.1-2 pp. 172
- Bovine rhinitis B virus, Foot-and-mouth disease virus, aerosols, animal disease models, foot-and-mouth disease, host-pathogen relationships, hosts, immune response, in vivo studies, interferons, mutants, neutralization, neutralizing antibodies, pathogenesis, protein synthesis, proteinases, steers, swine, viral proteins, virulence, virus replication, viruses
- Our recent study has shown that bovine rhinovirus type 2 (BRV2), a new member of the Aphthovirus genus, shares many motifs and sequence similarities with foot-and-mouth disease virus (FMDV). Despite low sequence conservation (36percent amino acid identity) and N- and C-terminus folding differences, the modeled BRV2 L^pro overall structure was comparable to the FMDV counterpart. The FMDV L^pro has been shown to be dispensable for virus replication but exerts important functions in its interaction with the host. In order to determine if the BRV2 L^pro could functionally replace that of FMDV, we generated a chimeric virus (A24LBRV3DYR) by exchanging the L^pro -coding region and carrying a negative antigenic marker built in the 3D^pol protein. In BHK-21 cells, the A24LBRV3DYR virus exhibited plaque morphology and titers similar to the parental A24WT virus. However, the A24LBRV3DYR profile of type 1 interferon activity in infected bovine cells resembled that of mutant A24LL virus that lacks L^pro, but this effect was less pronounced for porcine cells infected with this virus. Evaluation of the chimeric virus indicated that it effectively induces cleavage of eukaryotic initiation factor eIF4G in bovine cells. In vivo studies showed that the A24LBRV3DYR virus is attenuated in cattle using an aerosol route of infection, and exhibited low virulence in pigs exposed by contact to the mutant virus. The two steers aerosol inoculated with the chimeric virus produced neutralizing antibodies that protected them from generalized FMD following challenge with parental A24WT. These results provide evidence of functional relations among Aphthovirus L^pro, by cleaving eIF4G, inhibiting host-cell protein translation, and playing important roles on pathogenesis in natural hosts.