The immune response in mice and sheep to an aromatic-dependent mutant of Salmonella typhimurium and expressed heterologous antigens

Brennan, Francis Richard (1992) The immune response in mice and sheep to an aromatic-dependent mutant of Salmonella typhimurium and expressed heterologous antigens. PhD thesis, University of Glasgow.

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Abstract

An aromatic-dependent [aroA] mutant of an ovine isolate of Salmonella typhimurium, S25/1, was shown to be avirulent and have a much reduced capacity to invade the organs of both conventional mice and sheep when compared with the virulent parent strain. Oral vaccination with the aroA strain resulted in the production of Salmonella-specific immune responses in both mice and sheep, and the magnitude of these responses was related to the levels of tissue colonisation by the avirulent salmonellae. In vaccinated mice, high levels of Salmonella-specific IgM, IgG and IgA were detected in the serum, specific intestinal IgA was produced and there was evidence of specific cellular immunity. In vaccinated sheep, specific serum IgM was produced although specific IgG responses were very low and there was no evidence of specific coproantibody or specific T cells. Despite the different immune responses engendered in mice and sheep, both species were highly protected from high lethal challenge doses of the wildtype strain. The ability of the S25/laroA strain to deliver recombinant heterologous antigens to the immune system of both mice and sheep was investigated. Strains expressing the major outer membrane protein [MOMP] of Chlamydia nsittaci were shown to colonise murine tissues to similar levels as the non-recombinant strain and produced MOMP in vivo. MOMP-specific serum antibody and MOMP-specific intestinal IgA were detected in some mice, although these responses were low when compared with those to Salmonella, and there was no evidence of MOMP-specific T cells. In conventional lambs, no specific responses to MOMP could be detected, although the responses to Salmonella were very low in these animals. The aroA strain was also constructed to produce the leukotoxin [cytotoxin] of Pasteurella haemolvtica Al, however in vivo expression of the protein was very low. Consequently, only a small number of mice were seen to produce leukotoxin-specific antibody, and specific cell-mediated immunity was absent. When the strain was administered to germ-free lambs, reversion to virulence was seen which revealed instabilities in the vaccine strain, and in vivo expression of the protein was virtually lost after 24 h. Although there was no evidence of leukotoxin-specific antibody, leukotoxin specific cellular responses were demonstrated. However the low responses to Salmonella and the reversion to virulence seen in these lambs question the specificity of these responses. This study therefore demonstrated the ability of a live Salmonella aroA strain to engender specific immune responses and to confer protection against experimental salmonellosis. However, although the vaccine vector potential of the strain was not clearly demonstrated, some of the problems associated with expression of foreign antigens in Salmonella were revealed allowing optimal strategies for expression to be applied in future studies.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: David Baird
Keywords: Immunology
Date of Award: 1992
Depositing User: Enlighten Team
Unique ID: glathesis:1992-72407
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 24 May 2019 15:12
Last Modified: 24 May 2019 15:12
URI: http://theses.gla.ac.uk/id/eprint/72407

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