A partial deletion in non-structural protein 3A can attenuate foot-and-mouth disease virus in cattle

Abstract

The role of non-structural protein 3A of foot-and-mouth disease virus (FMDV) on the virulence in cattle has received significant attention. Particularly, a characteristic 10-20 amino acid deletion has been implicated as responsible for virus attenuation in cattle: a 10 amino acid deletion in the naturally occurring, porcinophilic FMDV O1 Taiwanese strain, and an approximately 20 amino acid deletion found in egg-adapted derivatives of FMDV serotypes O1 and C3. Previous reports using chimeric viruses linked the presence of these deletions to an attenuated phenotype in cattle although results were not conclusive. We report here the construction of a FMDV O1Campos variant differing exclusively from the highly virulent parental virus in a 20 amino acid deletion between 3A residues 87-106, and its characterization in vitro and in vivo. We describe a direct link between a deletion in the FMDV 3A protein and disease attenuation in cattle.

Interaction of Foot-and-Mouth Disease Virus Nonstructural Protein 3A with Host Protein DCTN3 Is Important for Viral Virulence in Cattle

“…Interestingly, O1C3A-PLDGv, replicated at a rate similar to the parental virus in FPK cells (data not shown). A similar replication pattern is observed with FMDV O/TAW/97 (28) and with a recently reported recombinant FMDV O1Cv virus harboring a deletion in 3A between residues 87 to 106 (therefore lacking the DCTN3 binding site) (12). Perhaps binding between FMDV 3A and host DCTN3 may contribute to the host range specificity of the virus.…”

“…The results demonstrated that viruses O1Cv and O1C3A-PLDGv both produced a similar large plaque size in LFBK-␣V␤6 cells. However, while virus O1Cv produced smaller plaques in FBK cells than those produced in LFBK-␣V␤6 cells, virus O1C3A-PLDGv was completely unable to produce any visible plaques, similarly to what has been previously described in O/TAW/97 (12). Thus, the substitution in 3A harbored by O1C3A-PLDGv virus undermined its ability of the virus to replicate in primary bovine cell cultures.…”

“…A similar deletion, consisting of 10 amino acids, was also observed (9) in the FMDV isolate responsible for an outbreak of FMD in Taiwan in 1997 (O/TAW/97) that severely affected swine but did not spread to cattle (10,11). This association between the presence of a specific deletion in this particular area of 3A and attenuation of virus virulence in cattle was recently confirmed using a recombinant O1 Campos virus harboring a 20-amino-acid deletion (12). The likely role for 3A in virulence and host range suggests that interactions with host factors underlie 3A's variability and the diversifying selection predicted to act upon it.…”

“…Our previous study analyzing the specific effect of the deletion in 3A and the effect on virulence in bovine (12), and the inability of DCTN3 to bind FMDV O/TAW/97, suggests the possibility that the host range could be determined by the ability of 3A to bind DCTN3; however, the DCTN3 protein appears to be highly conserved between swine and bovine, sharing 96% of the amino acid residues between species, so further experimentation would have to be done to determine whether the small differences in DCTN3 between species is responsible for the changes in host range determined with FMDV O/TAW.…”

Use of recombinant capsid proteins in the development of a vaccine against the foot-and-mouth disease virus

“…32 Variants of FMDV with deletions within the 3A protein have been identified; these are associated with more restricted host range of the virus including attenuation in cattle. 34 As indicated above, the 3C protein is a chymotrypsin-like protease and is responsible for most of the proteolytic cleavages within the virus encoded polyprotein (see Figure 2). In contrast to poliovirus (PV) and other enteroviruses, which require 3CD as the active protease for P1 processing, the FMDV 3C…”