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OD1611 Innate and vaccine-induced resistance to bovine respiratory pathogens Executive Summary Respiratory infections of livestock are a major animal welfare problem and pose a considerable financial burden to U.K agriculture. Outbreaks of respiratory disease may be associated with a single pathogen or be the result of a secondary bacterial infection following a primary virus infection. Irrespective of the aetiology, treatment of the disease invariably involves the use of antibiotics. The widespread use of antibiotics in livestock contributes to the emergence of antibiotic-resistant organisms, which pose a risk to human health. Lung infections are initiated either by inhalation of air-borne organisms or by direct contact with other infected animals leading to infection in the upper respiratory tract with subsequent spread to the lungs. Alveolar macrophages found in the airspaces of the lung represent a first line of defence against such pathogens. For those organisms that breach the lung epithelial lining, additional populations of phagocytic cells, e.g. neutrophils, macrophages and dendritic cells represent a second line of defence. These populations of cells operate not only by ingesting and destroying foreign organisms, but also by producing inflammatory mediators that recruit more phagocytic cells to local sites of infection, and by acting as antigen-presenting cells for stimulating T cell-mediated immune responses. Many of the organisms that cause respiratory disease subvert these functions and in some instances are also able to establish infection within these cell types. These properties of pathogens are not only important in enabling them to establish infection, but can increase the susceptibility of the lung to infection with other microorganisms. One such pathogen is bovine respiratory syncytial virus (BRSV), which is a major cause of lower respiratory tract disease in young calves. In this study we have demonstrated that although BRSV grows poorly or not at all in bovine alveolar macrophages (BAM), it influences the expression of a variety of molecules on the surface of the cell, some of which serve as receptors for bacteria. Furthermore, BRSV infection of BAM resulted in impaired killing of other respiratory pathogens, such as Mycoplasma bovis and Mycobacterium bovis, in vitro. These studies demonstrate that the interaction of BRSV with alveolar macrophages may contribute to a breakdown in local pulmonary defences and predispose the lung to infection by other pathogens. Further studies demonstrated that BRSV infection, in vivo, induced a transient reduction in the T cell response to PPD in BCG-vaccinated calves. This transient immunosuppression suggests another possible mechanism by which BRSV could predispose the calf to superinfection and also suggests that BRSV infection could interfere with the diagnosis of bovine TB. These studies indicate that the development of an effective vaccine against BRSV would not only protect against infection with this virus, but would also reduce the incidence of microbial superinfection and consequently reduce the use of antibiotics. The development of effective vaccines against respiratory pathogens based on traditional, empirical approaches has had only limited success and developments in recombinant DNA technology have created new opportunities for vaccine development. Vaccine development against BRSV has been hampered by the ability of RSV vaccines to augment respiratory disease. Severe respiratory disease has been seen in calves given inactivated BRSV vaccines and some such vaccines have been withdrawn from the market because of safety problems. The investigation of vaccine design and delivery for induction of protective immune responses in the bovine respiratory tract will lead to the development of validated methods and standard operating procedures that will provide a means of assessing and predicting the efficacy of candidate vaccine components and delivery systems. In this project a formalin-inactivated (FI) BRSV vaccine formulated in alum, which was immunogenic, failed to protect against BRSV infection and induced a more rapid onset of respiratory disease than that seen in control calves. In contrast, mucosal immunisation with live, mutant, attenuated BRS viruses induced almost complete protection against subsequent BRSV infection. These studies highlighted the importance of the non-structural (NS) proteins as virulence determinants of BRSV and suggested a role for a fusion protein virokinin in BRSV pathogenesis. Viruses in which the NS genes were deleted were more attenuated than viruses containing mutations in the cleavage sites of the fusion protein. Further studies suggested that the ability of the NS2 mutant to induce type I interferon and/or chemokines may contribute to the immunogenicity of this virus. The demonstration that NS deletion mutants are highly attenuated in young calves and induce protective immunity indicates that these viruses, and rBRSVDNS2 in particular, are promising candidates for vaccine development. The findings from this project have led to the identification of properties of the virus that can be targeted for attenuation and will contribute to the development and screening of attenuated virus strains for vaccination. These findings will contribute to Defra’s objectives of developing biological disease control strategies that will reduce the risk to consumers and to the environment from the persistence of residues of medicinal products in meat and other animal product