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  • CHEMISTRY; METALLURGY
    • BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
      • MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF (biocides, pest repellants or attractants, or plant growth regulators, containing micro-organisms, viruses, microbial fungi, enzymes, fermentates or substances produced by or extracted from micro-organisms or animal material A01N63/00; food compositions A21, A23; medicinal preparations A61K; chemical aspects of, or use of materials for, bandages, dressings, absorbent pads or surgical articles A61L; fertilisers C05); PROPAGATING, PRESERVING OR MAINTAINING MICRO-ORGANISMS (preservation of living parts of humans or animals A01N1/02); MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (micro-biological testing media C12Q)
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Bibliografia
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Bonanni, D., Rindi, L., Lari, N. & Garzelli, C. (2005). Immunogenicity of mycobacterial PPE44 (Rv2770c) in Mycobacterium bovis BCG-infected mice. J Med Microbiol 54, 443-448.

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Dainese, E., Rodrigue, S., Delogu, G. & other authors (2006). Posttranslational Regulation of Mycobacterium tuberculosis Extracytoplasmic-Function Sigma Factor {sigma}L and Roles in Virulence and in Global Regulation of Gene Expression. Infect Immun 74, 2457-2461.

Darwin, A. J. (2005). The phage-shock-protein response. Mol Microbiol 57, 621-628.
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Dieli, F., Troye-Blomberg, M., Ivanyi, J. & other authors (2001). Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vgamma9/Vdelta2 T lymphocytes. J Infect Dis 184, 1082-1085.

Dubrac, S. & Touati, D. (2000). Fur positive regulation of iron superoxide dismutase in Escherichia coli: functional analysis of the sodB promoter. J Bacteriol 182, 3802-3808.

Ferrara, G., Losi, M., Meacci, M. & other authors (2005). Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 172, 631-635.

Gey Van Pittius, N. C., Gamieldien, J., Hide, W., Brown, G. D., Siezen, R. J. & Beyers, A. D. (2001). The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria. Genome Biol 2, RESEARCH0044.

Giacomini, E., Sotolongo, A., Iona, E. & other authors (2006). The infection of human dendritic cells with a Mycobacterium tuberculosis sigE mutant stimulates a high production of IL-10 and low expression of CXCL10: impact on T cell response. Infect Immun Accepted for publication.

Hall, H. K. & Foster, J. W. (1996). The role of fur in the acid tolerance response of Salmonella typhimurium is physiologically and genetically separable from its role in iron acquisition. J Bacteriol 178, 5683-5691.

Hestvik, A. L., Hmama, Z. & Av-Gay, Y. (2005). Mycobacterial manipulation of the host cell. FEMS Microbiol Rev 29, 1041-1050.

Hsu, T., Hingley-Wilson, S. M., Chen, B. & other authors (2003). The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc Natl Acad Sci U S A 100, 12420-12425.

Loprasert, S., Sallabhan, R., Whangsuk, W. & Mongkolsuk, S. (2000). Characterization and mutagenesis of fur gene from Burkholderia pseudomallei. Gene 254, 129-137.

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Manganelli, R., Voskuil, M. I., Schoolnik, G. K. & Smith, I. (2001). The Mycobacterium tuberculosis ECF sigma factor SigE: role in global gene expression and survival in macrophages. Mol Microbiol 41, 423-437.

Manganelli, R., Voskuil, M. I., Schoolnik, G. K., Dubnau, E., Gomez, M. & Smith, I. (2002). Role of the extracytoplasmic-function Sigma Factor SigH in Mycobacterium tuberculosis global gene expression. Mol Microbiol 45, 365-374.

Manganelli, R., Fattorini, L., Tan, D., Iona, E., Orefici, G., Altavilla, G., Cusatelli, P. & Smith, I. (2004a). The Extra Cytoplasmic Function Sigma Factor SigE Is Essential for Mycobacterium tuberculosis Virulence in Mice. Infect Immun 72, 3038-3041.

Manganelli, R., Provvedi, R., Rodrigue, S., Beaucher, J., Gaudreau, L. & Smith, I. (2004b). Sigma factors and global gene regulation in Mycobacterium tuberculosis. J Bacteriol 186, 895-902.

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Oku, Y., Kurokawa, K., Ichihashi, N. & Sekimizu, K. (2004). Characterization of the Staphylococcus aureus mprF gene, involved in lysinylation of phosphatidylglycerol. Microbiology 150, 45-51.

Panina, E. M., Mironov, A. A. & Gelfand, M. S. (2003). Comparative genomics of bacterial zinc regulons: enhanced ion transport, pathogenesis, and rearrangement of ribosomal proteins. Proc Natl Acad Sci U S A 100, 9912-9917.

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Keywords
MICROBIOLOGY, MYCOBACTERIA, TRANSCRIPTIONAL REGULATION, TUBERCULOSIS, FUNCTIONAL GENOMICS, VIRULENCE, BACTERIAL GENETICS, PLASMIDS, MYCOBACTERIUM TUBERCULOSIS

From the study of global regulation of gene expression to the study of virulence in Mycobacterium tuberculosis

Università degli Studi di Padova
Abstract
Mycobacterium tuberculosis (Mtb) is an important pathogen responsible of about 2 million deaths every year, and estimated to infect about one third of the human population. Mtb has developed the ability to use complex networks of gene regulation; this characteristic, which is typical in environmental bacteria, represents a peculiarity of Mtb since obligate pathogens, such as intracellular pathogens, have evolved to survive in environments with relatively stable characteristics and therefore usually possess rather simple networks of gene regulation.
In this project we propose to start from the characterization of Mtb regulatory networks to distinguish which strategies are chosen during infection in order to identify new targets that could be used to develop new vaccines or therapeutic approaches.
The first task will be that to construct an inducible gene expression system in Mtb. Inducible systems are very important to study genes whose function is unknown since they allow to dose their activity following simple stimuli such as the addition of a metabolite to the culture medium. They represent an important tool in the study of new regulatory proteins, essential genes, or virulence genes.
The second objective will be that to characterize three sigma factors (SigG, SigJ and SigI) and two members of the Fur regulator family (FurA and FurB). These regulators will be studied with the help of mutants recently obtained in our laboratories and with the help of >>>

Principal Investigator
Riccardo Manganelli Università degli Studi di PADOVA
Research Objectives
Mycobacterium tuberculosis (Mtb) is an important pathogen responsible of about 2 million deaths every year, and estimated to infect about one third of the human population. At present, the only available vaccine is represented by the Mycobacterium bovis attenuated strain BCG which was developed at the Pasteur Institute about one century ago. This vaccine protects efficiently children affected by systemic infections such as tubercular meningitides, or miliary tuberculosis but it does not protect adults from the pulmonary forms of tuberculosis. Moreover, multi-drug resistant strains have recently appeared, causing the medical treatment of this disease more difficult. It is therefore necessary to better understand the pathogenic mechanism and the complex relationship between Mtb and the immune system to exploit new strategies and characterize new molecular targets in order to discover innovative drugs.
Mtb has developed the ability to use complex networks of gene regulation; this characteristic, which is typical in environmental bacteria, represents a peculiarity of Mtb since obligate pathogens, such as intracellular pathogens, have evolved to survive in environments with relatively stable characteristics and therefore usually posses rather simple networks of gene regulation.
Our approach to study Mtb begins from the characterization of its networks controlling global gene expression to distinguish what strategies are chosen during infection in order to survive >>>

Timescale
24 months
National and international background
In spite of the optimistic expectations of the 70s, predicting the complete eradication of Mycobacterium tuberculosis (Mtb) within the year 2000, tuberculosis (TB) is still a very important infection and in 1993 WHO declared TB a “global emergency”. It is calculated that about one third of the human population is affected by latent TB and about 2 million people are killed every year by TB (Raviglione, 2003). The lack of an efficient vaccine and of new antitubercolar drugs is in part due to the fact that until a few years ago the study of Mtb (and of the other mycobacteria) was neglected. (Smith, 2003), both for the real difficulties to work with this important pathogen (need of a BL3 level of containment, slow growth ...) and for the lack of interest due to the optimism regarding its eradication. The situation changed drastically starting from 1993, when WHO declared the planetary alarm. Since then the Mtb field became one of the most competitive and productive field of microbiology. Nevertheless, the knowledge regarding Mtb physiology and pathogenetic mechanisms (of basic interest to design new drugs and novel vaccines) is still not comparable with that available for other bacterial pathogens (Smith, 2003).
Upon its arrival in lung alveoli, Mtb is fagocitated by alveolar macrophages where it can replicate after blocking fagosome maturation at the stage of early endosome (Hestvik et al., 2005). Depending on the host immune response, Mtb can start an acute primary >>>