The roles of genes responsible for the survival and persistence of Brucella in the
host and the relationship between these genes and the disease were investigated via
signature-tagged transposon mutagenesis. As much as 8% of the Brucella genome is
important for survival of this organism in the host. This is an unusually high number
and may help to explain the chronic or persistent nature of Brucella infections. Mutants
attenuated in the mouse model were divided into two groups. The early mutants failed
to establish infection or colonize the host. The late mutants colonized the host but failed
to maintain infection. The vaccine potential of two mutants (virB10 and gcvH) that were
unable to sustain infection was compared to that of a vaccine strain, S19. Survival of
strain S19 in vivo was up to 12 weeks while virB10 and gcvH mutants were cleared from
spleen at 8, and 24 weeks post-inoculation, respectively. Mice were vaccinated with
individual mutants and then challenged with virulent S2308 at 8, 16, and 24 weeks postvaccination.
As a result, protective immunity correlated with persistence of the mutant
strain [gcvH>virB10]. These results suggest that survival is one of several factors that may influence
protective immunity making it difficult to compare strains. For example, examination of
host immune response revealed a similar pattern of host immune function (TH1 over
TH2) in all mice except those vaccinated with virB10 mutant. Since gcvH mutant
provided the best immunity, experiments were designed to explore its contribution of
persistence to protection. In an effort to reduce non-specific activation induced by
prolonged survival of gcvH mutant, protection was monitored after different periods of
vaccination exposure followed with doxycycline treatment. In these studies, persistence
of gcvH mutant enhanced protection against challenge. Overall, defined mutations in
genes affecting survival may render mutants as vaccine candidates capable of
stimulating protective immunity equal to or better than fortuitously isolated attenuated
strains. Future studies should focus on characterization of these and other genes
responsible for the persistence of Brucella to improve the safety and efficacy of live
vaccines.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/4163 |
| Date | 30 October 2006 |
| Creators | Hong, Priscilla Christine |
| Contributors | Ficht, Thomas A., Samuel, James E., Skare, Jon T., |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | 2433600 bytes, electronic, application/pdf, born digital |
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