Differential mosaicism of recombinant foot-and-mouth disease viruses resulting from heterologous superinfection of cattle

Evidence from both field and experimental studies suggests that recombination is a common feature in the evolution of foot-and-mouth disease virus (FMDV). Recent studies have demonstrated that heterologous superinfection of cattle persistently infected with FMDV leads to rapid generation of inter-serotypic recombinant viruses in the upper respiratory tract mucosa. The current study demonstrates that the order of exposure to FMDV strains A24 Cruzeiro and O1 Manisa substantially influenced the patterns of mosaicism of resultant recombinants. FMDV recombinants were isolated from oropharyngeal fluid samples from 7 of 12 cattle following heterologous superinfection at 21 days post-initial infection. There was no apparent competitive advantage of either parental virus. However, recombinant viruses recovered from six of seven animals had gained, or regained through multiple recombination events, the capsid-coding sequence of FMDV O1 Manisa despite the presence of high titers of neutralizing antibodies against that virus. Additionally, a sub-genomic region of high amino acid diversity, spanning the 3' portion of 3A through 3B, was derived from FMDV A24 in most of the recovered recombinants. Despite the frequent recovery of FMDV recombinants from the upper respiratory tract of superinfected animals, there was no detection of recombinant viruses in blood or lesions in the subset of animals that developed clinical foot-and-mouth disease during superinfection. Overall, these findings confirm the high frequency at which FMDV recombination occurs when persistently infected carrier cattle are exposed to a heterologous virus and reaffirm that superinfection of carriers should be considered as a source of FMDV genetic diversity in endemic regions.IMPORTANCEFoot-and-mouth disease virus (FMDV) is a pathogen of domestic livestock with profound global socioeconomic impacts. FMDV causes a subclinical persistent infection in ruminant hosts, such as cattle, during which the animals may become sequentially infected by heterologous variants of the virus. Our previous works have demonstrated that such superinfections frequently lead to emergence of novel recombinant virus variants in the upper respiratory tracts of infected animals. This current investigation demonstrates that the order in which the animals are exposed to two different viruses substantially influences the structure of resultant recombinant genomes and confirms the frequency at which FMDV recombination occurs following heterologous superinfection of persistently infected FMDV carriers.