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Title: Characterization of a chimeric foot-and-mouth disease virus bearing bovine rhinitis B virus leader proteinase

item UDDOWLA, SABENA - Oak Ridge Institute For Science And Education (ORISE)
item Pacheco Tobin, Juan
item LARSON, CHRISTOPHER - Oak Ridge Institute For Science And Education (ORISE)
item Bishop, Elizabeth
item Rodriguez, Luis
item RAI, DEVENDRA - Oak Ridge Institute For Science And Education (ORISE)
item Arzt, Jonathan
item Rieder, Aida - Elizabeth

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/29/2013
Publication Date: 10/1/2013
Citation: Uddowla, S., Pacheco Tobin, J., Larson, C., Bishop, E.A., Rodriguez, L.L., Rai, D., Arzt, J., Rieder, A.E. 2013. Characterization of a chimeric foot-and-mouth disease virus bearing bovine rhinitis B virus leader proteinase. Virology. 447(1-2):172-180.

Interpretive Summary: Foot and mouth disease virus (FMDV) causes a devastating disease (FMD) in livestock and represents a major threat to US agriculture exports and food security. Infection of cattle with FMDV usually initiates in the respiratory tract (throat and lungs) before generalizing and causing painful blisters in the mouth and feet. The closest genetic relative of FMDV is bovine rhinitis virus 2 (BRV2), a virus that causes respiratory disease in cattle. In our search for effective FMDV vaccines, we substituted the FMDV leader proteinase (FMDV L^pro, a viral protein that determines viral virulence) with that of BRV2. The resulting virus grew well in tissue culture and caused attenuated FMD in animals, suggesting that BRV L^pro only partially replaced the FMDV L^pro functions. This information will ultimately be applied to the development of attenuated FMDV strains that could be utilized as potential vaccines.

Technical Abstract: 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.