Download OD1611 Innate and vaccine-induced resistance to bovine

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