Role of Nonstructural Proteins 3A and 3B in Host Rangeand Pathogenicity of Foot-and-Mouth DiseaseVirus

Abstract

The genome of foot-and-mouth disease virus (FMDV) differs from that of other picornaviruses in that it encodes a larger 3A protein (>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 to 102 of the 153-codon 3A protein is associated with an inability of a Taiwanese Foot-and-mouth disease (FMD) is an extremely contagious viral disease of cattle, pigs, sheep, goats, and many wild animals. The disease is characterized by fever and vesicular lesions of the epithelium of the mouth, tongue, feet, and teats. The causal agent, FMD virus (FMDV), is a positive-stranded RNA virus that is the type species of the Aphthovirus genus of the Picornaviridae. The FMDV genome is over 8 kb in length and contains a protein cap (3B, also known as VPg) (27). During replication, the genome is expressed as a single open reading frame (ORF) that is processed into mature polypeptide products. Translation of the ORF begins with a proteinase (L pro ), which is followed in the ORF by the structural proteins (1A, 1B, 1C, and 1D), a short autoproteinase (2A), and the remaining nonstructural proteins (2B, 2C, 3A, 3B, 3C pro , and 3D pol ). 3C pro is responsible for proteolytic cleavage of the majority of the cleavage sites in the FMDV polyprotein (33), and 3D pol is the core subunit of the picornavirus RNA-dependent RNA polymerase (7). Protein 3B, which is represented in three nonidentical copies in FMDV (8), is covalently bound to the 5Ј end of the genome and antigenome, and functions in priming picornavirus RNA synthesis (see reference 34 for review). The functions of the nonstructural proteins 2B, 2C, and 3A are less well understood, although all three have hydrophobic domains (9, 26), and all have been found physically associated with intracellular membranes that proliferate in picornavirus-infected cells (2,3,29,30,32).We have previously shown that a deletion in the 3A protein of FMDV is a characteristic of a virus (O/TAW/97) that devastated the Taiwanese pork industry in 1997 and that the deleted 3A is responsible for the virus' inability to cause disease in cattle (1). However, this deleted 3A does not interfere with production of an acute and highly and readily transmissible disease in pigs (5). The deletion in O/TAW/97 occurs at positions 93 to 102 of the 153-amino-acid 3A protein and is similar in size and position to deletions that were found in eggadapted derivatives of FMDV that were developed for use as vaccines in South America (12). Interestingly, an investigation of the 3A coding regions of a number of Asian serotype O FMDVs revealed that viruses harboring this deletion have been circulating in Asia for more than 30 years and that viruses with 3As harboring a deletion spanning residues 133 to 143 have been circulating in Southeast Asia since the mid 1990s (18). Recently, Sobrino and coworkers have shown that adaptation of an FMDV isolate to cause disease in guinea pigs is dependent on a point mutation in 3A, adding further supp...

Comparative Genomics of Foot-and-Mouth Disease Virus

“…The 3B C-terminal regions contained more amino acid variability, including the majority of observed nonconservative substitutions and the fewest invariant residues. Notably, 3B3 was highly conserved in all isolates examined, supporting previous experimental evidence indicating that only this 3B isoform is essential for virus viability (26,84). 3B1 and 3B2 were more variable, and in fact, contained residues predicted here to undergo diversifying selection (3B1 residues 4 and 11 and 3B2 residues 17, 18, and 19).…”

“…3B1 and 3B2 were more variable, and in fact, contained residues predicted here to undergo diversifying selection (3B1 residues 4 and 11 and 3B2 residues 17, 18, and 19). These data, in conjunction with experimental data indicating that the deletion of 3B1 and 3B2 may affect FMDV virulence and host range (84), suggest that, similar to that of 3A, 3B1 and 3B2 protein variability reflects host range-specific functions.…”

Intra-serotype SAT2 chimeric foot-and-mouth disease vaccine protects cattle against FMDV challenge

“…Chimeric, genome-length clones could form the basis for the rational engineering of viruses with improved structural features as vaccine seed viruses. Viruses can be engi-neered with structurally stabilising mutations to be less reliant on a faultless cold chain [25,26,51], with BHK-21 cell culture adap-tation and increased antigen yield [31] or defective FMDV can be generated with deletions in various parts of the genome [52][53][54]. Furthermore, viruses can be engineered with modifications incorporated into the genome to support serological differentiation of infected from vaccinated animals [33] for surveillance of FMD in sub-Saharan Africa.…”

Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus

“…In FMDV and human rhinoviruses, these proteins have been shown to be involved in host-cell tropism and virulence (Lomax & Yin, 1989;Beard & Mason, 2000;Knowles et al, 2001;Pacheco et al, 2003;Harris & Racaniello, 2005).…”