Genetic and Phenotypic Variation of Foot-and-Mouth Disease Virus during Serial Passages in a Natural Host

Abstract

Foot-and-mouth disease virus (FMDV), like other RNA viruses, exhibits high mutation rates during replication that have been suggested to be of adaptive value. However, even though genetic variation in RNA viruses and, more specifically, FMDV has been extensively examined during virus replication in a wide variety of in vitro cell cultures, very little is known regarding the generation and effects of genetic variability of virus replication in the natural host under experimental conditions and no genetic data are available regarding the effects of serial passage in natural hosts. Here, we present the results of 20 serial contact transmissions of the highly pathogenic, pig-adapted O Taiwan 97 (O Tw97) isolate of FMDV in swine. We examined the virus genomic consensus sequences for a total of 37 full-length viral genomes recovered from 20 in vivo passages. The characteristics and distributions of changes in the sequences during the series of pig infections were analyzed in comparison to the O Tw97 genomes recovered from serially infected BHK-21 cell cultures. Unexpectedly, a significant reduction of virulence upon pig passages was observed, and finally, interruption of the viral transmission chain occurred after the14th pig passage (T14). Virus was, however, isolated from the tonsils and nasal swabs of the asymptomatic T15 pigs at 26 days postcontact, consistent with a natural establishment of the carrier state previously described only for ruminants. Surprisingly, the region encoding the capsid protein VP1 (1D) did not show amino acid changes during in vivo passages. These data demonstrate that contact transmission of FMDV O Tw97 in pigs mimics the fitness loss induced by the bottleneck effect, which was previously observed by others during plaque-to-plaque FMDV passage in vitro, suggesting that unknown mechanisms of virulence recovery might be necessary during the evolution and perpetuation of FMDV in nature.Foot-and-mouth disease (FMD) has a high economical impact, affecting domestic and wild cloven-hoofed animal species worldwide (reviewed in references 2, 3, 24, and 46). The etiological agent FMD virus (FMDV) of Picornaviridae occurs as seven distinct serotypes and multiple subtypes, reflecting significant genetic and antigenic heterogeneity. In the field, this heterogeneity is reflected by the lack of cross-protection even between intraserotype variants (2, 3, 46). VP1 (1D), the highly variable FMDV capsid protein with roles in virus entry, immunity, and serotype specificity, has been the subject of extensive comparative sequence analysis (reviewed in reference 22). These studies have shown cocirculation of FMDV genotypes in single outbreaks, with genotypes usually grouping into geographically and genetically distinct lineages (less than 15% nucleotide differences) known as topotypes (41). With the expansion of FMDV genomic databases, however, evidence is accumulating for the inadequacy of VP1 analysis alone for epidemiological studies and for the importance of recombination in FMDV evolution (4,20,23).The sel...

Foot and Mouth Disease Virus Genome

“…Using different recombination detection methods among the publicly available FMDV complete genome sequences, the large number of recombinant isolates suggests that horizontal recombination of sequences is common and www.intechopen.com probably advantageous in terms of fitness costs. Interestingly, the distribution of recombination breakpoints was found to be largely nonrandom (37,38). Results suggest that genome regions encoding the structural proteins are functionally interchangeable modules, as can be deduced from evidence that the structural and nonstructural coding regions of picornaviruses evolve largely independently of one another (see ref.…”

“…Indications of differential susceptibility for developing a subclinical course of disease has been observed in many instances: buffaloes and cattle present with different disease manifestations, with breed affecting severity (see ref. Most interestingly, pigs experimentally infected with a highly virulent porcine-tropic strain (OTw97) exhibited gradual loss of virulence and the establishment of a subclinical infection upon serial passage in the absence of FMDV-specific antibodies (38). However, experimental evidence of possible mechanisms of transmission and its effects on the FMDV genome are sparse; additional controlled experimentation in this field is required (32,33,38).…”

“…Results suggest that novel antigenic variants benefit from a selective advantage in their interaction with the immune system, possibly throughout the course of an infection and/or during transmission to individuals with previous exposure to antigen (see ref. 14,[36][37][38].…”

“…Results suggest that genome regions encoding the structural proteins are functionally interchangeable modules, as can be deduced from evidence that the structural and nonstructural coding regions of picornaviruses evolve largely independently of one another (see ref. 14,[37][38][39][40].…”

A Flexible Spatial Framework for Modeling Spread of Pathogens in Animals with Biosurveillance and Disease Control Applications

“…Disease progression parameters were taken from various literature sources. The incubation time for cattle is typically 4 to 8 days [36,37]. Pigs generally progress faster and can show symptoms 2 to 5 days after infection [27,38].…”