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Altered Transcriptome of the B. melitensis Vaccine Candidate 16M?vjbR, Implications for Development of Genetically Marked Live Vaccine.

ABSTRACT: The VjbR protein induced antibody responses in both human and animal brucellosis, and the vjbR mutant 16M?vjbR is an ideal vaccine candidate because of the feasibility of using the VjbR as diagnostic antigen. To further characterize this vaccine candidate and provide information for vaccine development, in the present study, a whole genome DNA microarray of 16M were used to compare the transcriptome of the vjbR mutant to that of the wild type strains. A total of 126 genes were greatly differentially expressed in the vjbR mutant. A great proportion of virB and flagellar genes were differentially expressed in the vjbR mutant, implying that the vjbR regulate expression of virulence genes by sensing intracellular environments. Interestingly, the virB genes are regulated by the vjbR in independent manners as shown by their different fold changes and transcription abundances. A number of genes involved in translation, stress response, amino acid transport and metabolism, cell wall/membrane biogenesis, energy production and conversion, translation were differentially expressed. The vjbR mutant showed increased sensitivity to stresses of nutrition limitation, oxidative stress and acidification, and decreased survival in macrophage and mice, being consistent with its transcription profiles. These results indicated that the quorum sensing regulator vjbR could sense intracellular environments and response to them by regulate expression of virulence genes and other intracellular survival related genes, and therefore contribute to Brucella survival in host cells. This also provided direct evidence for the rational vaccine design by using antigenic global regulator for future development of genetically marked vaccine for brucellosis.

SUBMITTER: Ke Y

PROVIDER: S-EPMC3516643 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Altered Transcriptome of the B. melitensis Vaccine Candidate 16MΔvjbR, Implications for Development of Genetically Marked Live Vaccine.

Ke Yuehua Y Wang Yufei Y Yuan Xitong X Zhong Zhijun Z Qu Qing Q Zhou Dongsheng D Zeng Xiaotao X Xu Jie J Wang Zhoujia Z Du Xinying X Wang Tongkun T Yang Ruifu R Zhen Qing Q Yu Yaqin Y Huang Liuyu L Chen Zeliang Z

Indian journal of microbiology 20120802 4

The VjbR protein induced antibody responses in both human and animal brucellosis, and the vjbR mutant 16MΔvjbR is an ideal vaccine candidate because of the feasibility of using the VjbR as diagnostic antigen. To further characterize this vaccine candidate and provide information for vaccine development, in the present study, a whole genome DNA microarray of 16M were used to compare the transcriptome of the vjbR mutant to that of the wild type strains. A total of 126 genes were greatly differenti ...[more]

PMID: 24293713

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Project description:Many pathogenic bacteria use a regulatory process termed Quorum Sensing (QS) to produce and detect small diffusible molecules to synchronize gene expression within a population. In Gram-negative bacteria, the detection and response to these molecules depend on transcriptional regulators belonging to the LuxR family. Such a system have been discovered in the intracellular pathogen Brucella melitensis, a Gram-negative bacteria responsible for brucellosis, a word-wide zoonosis remaining a serious public health concern in endemic countries. Two LuxR-type regulators, VjbR and BabR, have been identified in the genome of this pathogen. The vjbR mutant is highly attenuated in all tested models suggesting a crucial role of QS in the virulence of Brucella. This attenuation is at least due to the involvement of VjbR in the activation of the virB operon coding for a type four secretion system essential for Brucella to reach its intracellular replication compartment. At present, no function has been attributed to BabR. To assess the role of both Brucella QS-regulators, we performed in tandem comparative transcriptomic and proteomic analyses of vjbR and babR mutants. These experiments revealed that 10% of Brucella genome is regulated through those regulators, revealing that QS is a global regulatory system in this intracellular pathogen. The overlapping between BabR and VjbR targets suggest an unexpected cross-talk between these two regulators. Moreover, our results demonstrate that VjbR and BabR regulate many gene and/or proteins involved in stress response, metabolism and virulence. These targets are potentially involved in the adaptation of Brucella to the oxidative, pH and nutritional stresses encountered within the host. These findings highlight the involvement of QS in the virulence of Brucella and led us to suggest that this regulatory system could be implied in the spatial and sequential adaptation of Brucella to the host environment. Keywords: Quorum Sensing, Comparative gene expression, Brucella melitensis

Project description:BackgroundQuorum sensing is a communication system that regulates gene expression in response to population density and often regulates virulence determinants. Deletion of the luxR homologue vjbR highly attenuates intracellular survival of Brucella melitensis and has been interpreted to be an indication of a role for QS in Brucella infection. Confirmation for such a role was suggested, but not confirmed, by the demonstrated in vitro synthesis of an auto-inducer (AI) by Brucella cultures. In an effort to further delineate the role of VjbR to virulence and survival, gene expression under the control of VjbR and AI was characterized using microarray analysis.ResultsAnalyses of wildtype B. melitensis and isogenic DeltavjbR transciptomes, grown in the presence and absence of exogenous N-dodecanoyl homoserine lactone (C12-HSL), revealed a temporal pattern of gene regulation with variances detected at exponential and stationary growth phases. Comparison of VjbR and C12-HSL transcriptomes indicated the shared regulation of 127 genes with all but 3 genes inversely regulated, suggesting that C12-HSL functions via VjbR in this case to reverse gene expression at these loci. Additional analysis using a DeltavjbR mutant revealed that AHL also altered gene expression in the absence of VjbR, up-regulating expression of 48 genes and a luxR homologue blxR 93-fold at stationary growth phase. Gene expression alterations include previously un-described adhesins, proteases, antibiotic and toxin resistance genes, stress survival aids, transporters, membrane biogenesis genes, amino acid metabolism and transport, transcriptional regulators, energy production genes, and the previously reported fliF and virB operons.ConclusionsVjbR and C12-HSL regulate expression of a large and diverse number of genes. Many genes identified as virulence factors in other bacterial pathogens were found to be differently expressed, suggesting an important contribution to intracellular survival of Brucella. From these data, we conclude that VjbR and C12-HSL contribute to virulence and survival by regulating expression of virulence mechanisms and thus controlling the ability of the bacteria to survive within the host cell. A likely scenario occurs via QS, however, operation of such a mechanism remains to be demonstrated.

Dataset Information

Altered Transcriptome of the B. melitensis Vaccine Candidate 16M?vjbR, Implications for Development of Genetically Marked Live Vaccine.

Publications

Altered Transcriptome of the B. melitensis Vaccine Candidate 16MΔvjbR, Implications for Development of Genetically Marked Live Vaccine.

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