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Title: ROLE OF NONSTRUCTURAL PROTEINS 3A AND 3B IN HOST RANGE AND PATHOGENICITY OF FOOT-AND-MOUTH DISEASE VIRUS

Author
item PACHECO, JUAN - OCID
item Henry, Tina
item O'DONNELL, VIVIAN - FORMER USDA,PIADC EMPLOYE
item GREGORY, JASON - FORMER USDA,PIADC EMPLOYE
item MASON, PETER - FORMER USDA,PIADC EMPLOYE

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/5/2003
Publication Date: N/A
Citation: N/A

Interpretive Summary: Foot-and-mouth disease (FMD) is an exotic disease that is the number-one foreign animal disease threat to the US. Severe export restrictions are imposed on countries that have FMD, so introduction to the US would have grave economic consequences for our livestock producers. In the spring of 1997, a new variant of the virus that causes FMD (FMDV strain O/TAW/97) emerged and devastated the Taiwanese pig population, resulting in the destruction of about 4 million pigs and a cost of over $6 billion. Interestingly, O/TAW/97 and a related virus we detected several years later (O/VIT/2/97) have a deletion in one of their proteins that appears to have arisen from laboratory manipulation to produce attenuated vaccines. To further investigate the role of this gene deletion in pathogenesis and spread, we engineered a panel of FMDVs and tested them in pigs. Our studies confirmed that deletions of this region of the viral nucleic acid genome could result in attenuation, but not to the point of production of useful live-attenuated vaccines to protect animals against FMD. Moreover, the complete blockage of growth of these genetically engineered viruses in cells derived from cattle suggested that the viruses with this deletions would not naturally arise in nature, where cattle transmission appears to be important for virus spread.

Technical Abstract: The genome of foot-and-mouth disease virus (FMDV) differs from that of other picornaviruses in that it encodes a larger 3A protein (over 50% longer than poliovirus 3A) as well as three copies of protein 3B (also known as VPg). Previous studies have shown that a deletion of amino acids 93-102 of the 153-codon 3A protein is associated with an inability of a Taiwanese strain of FMDV (O/TAW/97) to cause disease in bovines. Recently, an Asian virus with a second 3A deletion (amino acids 133-143) has also been detected (Knowles et al., 2001, J Virol 75:1551). Genetically engineered viruses harboring the 93-102 amino acid deletion or the 133-143 deletion grew well in porcine cells but replicated poorly in bovine cells, while a genetically engineered derivative of the O/TAW/97 virus expressing a full-length 3A (strain A12) grew well in both cell types. Interestingly, a virus with a deletion spanning amino acid 93-144 also grew well in porcine cells and caused disease in swine. Further, genetically engineered viruses containing only a single copy of VPg were readily recovered with the full-length 3A, the deleted 3A (93-102), or the "super" deleted forms of 3A (93-144). All of the single-VPg viruses were attenuated in porcine cells and replicated poorly in bovine cells. The single-VPg viruses produced a mild disease in swine indicating that VPg copy number is an important determinant of host range and virulence. The association of VPg copy number with increased virulence in vivo may help to explain why all naturally occurring FMDVs have retained 3 copies of VPg.