Brucella melitensis is the etiological agent of brucellosis, a zoonotic
disease characterized by abortions in ruminant animals and a chronic
debilitating disease in humans. Despite genome sequencing, little is known
about the genetic elements behind Brucella s ability to survive and cause
disease. Regulatory networks provide the ability to adapt to changing
environments by initiating expression from specific regulons to provide
adjustments to metabolism and mechanisms that enhance survival. Little detail
is known about transcriptional networks that exist in Brucella, but are of great
interest because they could provide information about genetic loci that contribute
to virulence and intracellular survival.
Transposon mutagenesis identified gene loci that are indispensable for
the intracellular replication of B. melitensis, including virulence genes, metabolic
defects, and transcriptional regulators. Two transcriptional regulators of interest
were identified, MucR and VjbR. VjbR is a LuxR homologue and is associated with the regulation of virulence genes in a density dependent manner in a
number of bacterial pathogens, and is consistent with VjbR regulation of
virulence genes in B. melitensis. Microarray analysis of vjbR and a potential
activating signal C12-HSL revealed that both regulate numerous putative
virulence genes, including adhesins, proteases, protein secretion/translocation
components, potential effector proteins, lipoproteins, a hemolysin and stress
survival aids. This analysis also revealed that C12-HSL is not an activating signal
of VjbR, but instead acts to suppress VjbR activity.
MucR is a transcriptional regulator shown to regulate exopolysaccharide
synthesis in the closely related Rhizobiales. Microarray analysis of a mucR
mutant in B. melitensis suggested that MucR contributes to the regulation of
nitrogen metabolism and iron sequestering/storage. MucR was also found to
regulate genes involved in stress response, regulating several proteases that
may contribute to enhanced survival and virulence of the organism.
This work identified approximately 1,000 genetic loci that may be
important to the survival of B. melitensis, revealing potential virulence genes and
metabolic defects. Interruption of the VjbR regulon could be a potential
chemotherapeutic target for the treatment of brucellosis. Furthermore, this work
describes the functions of two gene deletions that are being evaluated as novel
attenuated vaccines.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/ETD-TAMU-2970 |
| Date | 15 May 2009 |
| Creators | Weeks, Jenni Nichole |
| Contributors | Ficht, Thomas A |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | electronic, application/pdf, born digital |
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