Recombinant bovine respiratory syncytial virus with deletion of the SH gene induces increased apoptosis and pro-inflammatory cytokines in vitro, and is attenuated and induces protective immunity in calves

Bovine respiratory syncytial virus (BRSV) causes inflammation and obstruction of the small airways, leading to severe respiratory disease in young calves. The virus is closely related to human (H)RSV, a major cause of bronchiolitis and pneumonia in young children. The ability to manipulate the genome of RSV has provided opportunities for the development of stable, live attenuated RSV vaccines. The role of the SH protein in the pathogenesis of BRSV was evaluated in vitro and in vivo using a recombinant (r)BRSV in which the SH gene had been deleted. Infection of bovine epithelial cells and monocytes with rBRSV?SH, in vitro, resulted in an increase in apoptosis, and higher levels of tumor necrosis factor-? and interleukin-1? compared with cells infected with parental, wild-type (WT) rBRSV. Although replication of rBRSV?SH and WT rBRSV, in vitro, were similar, the replication of rBRSV?SH was moderately reduced in the lower, but not the upper, respiratory tract of experimentally infected calves. Despite the greater ability of rBRSV?SH to induce pro-inflammatory cytokines, in vitro, the pulmonary inflammatory response in rBRSV?SH-infected calves was significantly reduced compared to that in calves inoculated with WT rBRSV, 6 days previously. Virus lacking SH appeared to be as immunogenic and effective in inducing resistance to virulent virus challenge, 6 months later, as the parental rBRSV. These findings suggest that rBRSV?SH may be an ideal live attenuated virus vaccine candidate, combining safety with a high level of immunogenicity.