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Title: Role of the Region Located Between the Two AUG Initiation Codons in the Pathogenesis of Foot-and-Mouth Disease Virus (FMDV)

item Pacheco Tobin, Juan
item Pauszek, Steven
item Borca, Manuel
item Rieder, Aida - Elizabeth
item Rodriguez, Luis

Submitted to: European Study Group on the Molecular Biology of Picornaviruses
Publication Type: Abstract Only
Publication Acceptance Date: 3/27/2008
Publication Date: 5/26/2008
Citation: Piccone, M.E., Pacheco Tobin, J., Pauszek, S.J., Borca, M.V., Rieder, A.E., Rodriguez, L.L. 2008. Role of the Region Located Between the Two AUG Initiation Codons in the Pathogenesis of Foot-and-Mouth Disease Virus (FMDV). European Study Group on the Molecular Biology of Picornaviruses. p. 199.

Interpretive Summary:

Technical Abstract: Translation of the viral polyprotein in picornavirus initiates at an AUG located immediately after the IRES in the 5’UTR. In the case of foot-and-mouth disease virus (FMDV) there are two functional AUGs in this region separated by 84 nucleotides. The role of this region in the viral life cycle has remained elusive. To characterize the function of this region we generated and characterized a series of viruses by transposon (Tn)-mediated random insertion mutagenesis of a cDNA infectious clone of FMDV (pA24Cru). Mutants A24-L1115 and A24-L1123 contained 57 nt Tn insertions at positions 1115 and 1123 respectively. These viruses grew to a slightly lower titer and had a smaller plaque size phenotype than the parental virus (A24-wt) in hamster (BHK-21), bovine and swine cell lines and failed to produce plaques in primary lamb kidney cells. The insertion had no detectable effect on in vitro translation and processing of the viral polyprotein, but in infected cells A24-1123 showed a delay in the synthesis of the viral proteins compared to A24-wt. Mutant A24-L1094del which contained an in-frame 51 nucleotide deletion had similar phenotype to that of the parental virus both in in-vitro translation and in infected cells. When tested in-vivo by aerosol inoculation in cattle, A24-1094del (3/3 inoculated steers) caused clinical disease and virus distribution similar to that caused by the parental virus A24-wt. A24-1115 caused delayed clinical disease in 2 of 3 inoculated steers, but the virus recovered from them had deleted the Tn insert. In contrast three animals inoculated with A24-1123 and one inoculated with A24-1115 retained the Tn insert and did not show clinical signs or viremia, but neutralizing antibodies were detected in these animals indicating that virus infection had occurred. Virus distribution in animals sacrificed 24h after aerosol inoculation with A24-L1123 was more restricted than that observed for A24wt, A24-L1094del or A24-L1115 and was limited to few tissues in the pharyngeal region. This data identifies the inter-AUG region of FMDV as a virulence determinant in cattle. Understanding the role of FMDV genomic regions in pathogenesis is necessary for the development of novel strategies for prevention and control of this important disease.