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 rBRSVΔSH, in vitro, resulted in an increase in apoptosis, and higher levels of TNF-α and IL-1β compared with cells infected with parental, wild-type (WT) rBRSV. Although replication of rBRSVΔSH and WT rBRSV, in vitro, were similar, the replication of rBRSVΔSH was moderately reduced in the lower, but not the upper, respiratory tract of experimentally infected calves. Despite the greater ability of rBRSVΔSH to induce pro-inflammatory cytokines, in vitro, the pulmonary inflammatory response in rBRSVΔSH-infected calves was significantly reduced compared with 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 rBRSVΔSH may be an ideal live attenuated virus vaccine candidate, combining safety with a high level of immunogenicity.
Pirbright Institute, Woking, Surrey, GU24 0NF, UK.
Geraldine
G
Taylor
Pirbright Institute, Woking, Surrey, GU24 0NF, UK.
Sara
S
Wyld
Pirbright Institute, Woking, Surrey, GU24 0NF, UK.
Jean-Francois
JF
Valarcher
Pirbright Institute, Woking, Surrey, GU24 0NF, UK.
Efrain
E
Guzman
Pirbright Institute, Woking, Surrey, GU24 0NF, UK.
Michelle
M
Thom
Pirbright Institute, Woking, Surrey, GU24 0NF, UK.
Stephanie
S
Widdison
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Ursula J
UJ
Buchholz
D000818:Animals; D017209:Apoptosis; D002417:Cattle; D002418:Cattle Diseases / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis*; D017353:Gene Deletion; D005814:Genes, Viral; D006801:Humans; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control / Q000662:veterinary; D022261:Respiratory Syncytial Virus Vaccines / Q000235:genetics / Q000276:immunology; D018112:Respiratory Syncytial Virus, Bovine / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology / Q000472:pathogenicity; D012137:Respiratory System / Q000821:virology; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014774:Virulence / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D022261:Respiratory Syncytial Virus Vaccines; D015682:Retroviridae Proteins, Oncogenic; D014409:Tumor Necrosis Factor-alpha; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; C056150:small hydrophobic protein, virus