Project description:Tuberculosis (2004) 84, 188196 (www.elsevierhealth.com/journals/tube),Comparative expression studies of a complex phenotype: cord formation in Mycobacterium tuberculosis,Qian Gao, Katharine Kripke, Zuhre Arinc, Martin Voskuil, Peter Small
Project description:Identification of changes in microRNA expression, remodelling of relationships between microRNA and mRNA expression levels, and genetic polymorphisms associated with inter-individual variation in the dendritic cell immune response to Mycobacterium tuberculosis infection. We characterised genome-wide changes in microRNA expression, and of the broader miRNA-mdeiated regulatory system, in response to Mycobacterium tuberculosis (MTB) infection, and assessed the extent to which this response is under genetic control. To do so, we profiled microRNA expression levels in primary dendritic cells from 65 individuals before and after infection with MTB for 18 hours.
Project description:The PhoPR two-component system is essential for virulence in Mycobacterium tuberculosis where it controls expression of approximately 2% of the genes, including those for the ESX-1 secretion apparatus, a major virulence determinant. Mutations in phoP lead to compromised production of pathogen-specific cell wall components and attenuation both ex vivo and in vivo. Using antibodies against the native protein in ChIP-seq experiments (chromatin immunoprecipitation followed by high-throughput sequencing) we demonstrated that PhoP binds to at least 35 loci on the M. tuberculosis genome. The PhoP regulon comprises several transcriptional regulators as well as genes for polyketide synthases and PE/PPE proteins. Integration of ChIP-seq results with high-resolution transcriptomic analysis (RNA-seq) revealed that PhoP controls 30 genes directly, whilst regulatory cascades are responsible for signal amplification and downstream effects. The most prominent site of PhoP regulation was located in the intergenic region between rv2395 and PE_PGRS41, where the mcr7 gene codes for a small non-coding RNA (ncRNA). Northern blot experiments confirmed the absence of Mcr7 in the M. tuberculosis phoP mutant as well as low-level expression of the ncRNA in M. tuberculosis complex members other than M. tuberculosis. By means of genetic and proteomic analyses we demonstrated that Mcr7 modulates translation of the tatC mRNA thereby impacting the activity of the Twin Arginine Translocation (Tat) protein secretion apparatus. As a result, secretion of the immunodominant Ag85 complex and the beta-lactamase BlaC is affected, among others. Mcr7, the first ncRNA of M. tuberculosis whose function has been established, therefore represents a missing link between the PhoPR two-component system and the downstream functions necessary for successful infection of the host. ChiP-Seq: M. tuberculosis H37Rv (GC1237) cultures grown in vitro to exponential phase. Two wild type samples plus one isogenic phoP mutant as control
Project description:Jamshidi2007 - Genome-scale metabolic network
of Mycobacterium tuberculosis (iNJ661)
This model is described in the article:
Investigating the metabolic
capabilities of Mycobacterium tuberculosis H37Rv using the in
silico strain iNJ661 and proposing alternative drug
Jamshidi N, Palsson BØ.
BMC Syst Biol 2007; 1: 26
BACKGROUND: Mycobacterium tuberculosis continues to be a
major pathogen in the third world, killing almost 2 million
people a year by the most recent estimates. Even in
industrialized countries, the emergence of multi-drug resistant
(MDR) strains of tuberculosis hails the need to develop
additional medications for treatment. Many of the drugs used
for treatment of tuberculosis target metabolic enzymes.
Genome-scale models can be used for analysis, discovery, and as
hypothesis generating tools, which will hopefully assist the
rational drug development process. These models need to be able
to assimilate data from large datasets and analyze them.
RESULTS: We completed a bottom up reconstruction of the
metabolic network of Mycobacterium tuberculosis H37Rv. This
functional in silico bacterium, iNJ661, contains 661 genes and
939 reactions and can produce many of the complex compounds
characteristic to tuberculosis, such as mycolic acids and
mycocerosates. We grew this bacterium in silico on various
media, analyzed the model in the context of multiple
high-throughput data sets, and finally we analyzed the network
in an 'unbiased' manner by calculating the Hard Coupled
Reaction (HCR) sets, groups of reactions that are forced to
operate in unison due to mass conservation and connectivity
constraints. CONCLUSION: Although we observed growth rates
comparable to experimental observations (doubling times ranging
from about 12 to 24 hours) in different media, comparisons of
gene essentiality with experimental data were less encouraging
(generally about 55%). The reasons for the often conflicting
results were multi-fold, including gene expression variability
under different conditions and lack of complete biological
knowledge. Some of the inconsistencies between in vitro and in
silico or in vivo and in silico results highlight specific loci
that are worth further experimental investigations. Finally, by
considering the HCR sets in the context of known drug targets
for tuberculosis treatment we proposed new alternative, but
equivalent drug targets.
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Project description:Transcriptional profiling of SirR and manganese regulated expression of genes in Mycobacterium tuberculosis strains comparing high manganese vs. low manganese in Rv (wild type Mycobacterium tuberculosis) and ST70 (mntR mutant strain of Mycobacterium tuberculosis) Overall design: Two strains each with two conditions experiment, Rv (Mycobacterium tuberculosis wild type strain) high manganese vs. low manganese and ST70 (mntR mutant strain of Mycobacterium tuberculosis) high manganese vs. low manganese. Number of biological replicates is 3 for each condition for each strain.
Project description:Transcriptional profiling of SirR and manganese regulated expression of genes in Mycobacterium tuberculosis strains comparing high manganese vs. low manganese in Rv (wild type Mycobacterium tuberculosis) and ST70 (mntR mutant strain of Mycobacterium tuberculosis) Two strains each with two conditions experiment, Rv (Mycobacterium tuberculosis wild type strain) high manganese vs. low manganese and ST70 (mntR mutant strain of Mycobacterium tuberculosis) high manganese vs. low manganese. Number of biological replicates is 3 for each condition for each strain.