This project aims to study the relation between the cell cycle
and dormancy development in Mycobacterium tuberculosis (Mtb), with the final
aim being to increase the knowledge on dormancy development and to identify
potential candidates for the development of antitubercular drugs specifically
active in dormant bacilli. Mtb is a facultative intracellular pathogen
able to infect the human lung for decades without showing any symptom. Following
immunity suppression caused by age, diseases or malnutrition, tubercle
bacilli can reactivate as an overt disease.
About one third of the human population is estimated to be affected
by latent tuberculosis representing a huge reservoir for the infection.
The lack of drugs efficiently active on dormant bacteria is a major problem in
fighting this important disease. Conditional mutants unable to express important
cell cycle regulators will be constructed and used to study their role
in: global regulation of gene expression; cytolocalisation of cell cycle proteins,
and; latency development in vitro and in vivo.
Additionally, a transposon insertion library will be used to identify new
mycobacterial genes essential for survival to prolonged stationary
phase and their expression will be measured during progressive and latent
Upon Mtb arrival in the alveoli by inhalation of aerosol particles, it is engulfed
by alveolar macrophages. These cells are unable to kill Mtb,
which replicate in their phagosomes. Depending on the quality and intensity
of the immune response, Mtb will cause a primary acute infection or will be
walled off in granulome where it will be able to survive in latency for decades
without showing any symptom. In some individuals as the immune system
becomes weaker due to the age or to diseases such as AIDS, Mtb can reactivate,
escape from the granulome and cause a secondary acute infection.
About one third of the world population is believed to affected by
Active tuberculosis is a treatable infection. The main anti-tuberculosis
drugs are isoniazid, rifampicin, pyrazinamide, and ethambutol. Most
antitubercular drugs target cell wall or RNA synthesis and are thus more active
against actively growing bacteria. However, during latent tuberculosis,
proliferation appears to be markedly reduced or absent, so that latent bacilli
are less amenable to killing and very hard to eradicate. Although some
clinical trials have demonstrated that treatment of latent tuberculosis reduces
the presence of Mtb, the risk of reactivation is not completely eliminated.
To successfully treat patients affected by latent tuberculosis new drugs are
needed active against latent bacteria. These drugs should target bacterial
structures expressed during latency and essential for latency maintenance
and/or for reactivation. Alternatively, a different class of new drugs can be
used in order to interfere with the regulation of Mtb gene expression during
latency, forcing it to reactivate. Once bacteria are reactivated, they can be
efficiently removed by isoniazid or rifampicin.
The aim of this project is to increase the knowledge on dormancy development in Mycobacterium tuberculosis with particular focus on cell-cycle
related proteins and to identify potential candidates for the development
of antitubercular drugs specifically active against dormant bacilli.
Better characterisation of the physiology of dormancy and its relation to cellcycle proteins. Identification of new genes involved in dormancy development.
The identified genes will be excellent potential candidates for the development of new antitubercular drugs.
Dipartimento di Istologia, Microbiologia e Biotecnologie
Università di Padova
Tel: +39 0490272366
Fax: +39 0498272355
Université Descartes Paris V
156 rue de Vaugirard
75730 PARIS cedex 15
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Km 11 Carretera Panamericana
Altos de Pipe
Estdo Miranda, Venezuela
PO Box: Apartado 21827 Caracas
|Tel: +58 212 5041715|
Fax: +58 212 5041444
||Centro Nacional de Biotecnología
C/ Darwin 3
CSIC Campus de Cantoblanco
|Tel: +34 91 585 46 9
Fax: +34 91 585 45 06
||Rogelio Hernandez Pando
Experimental Pathology Section
Department of Pathology
National Institute of Medical Sciences
and Nutrition "Salvador Zubiran"
Street- Vasco de Quiroga, no-12,
Mexico city, Mexico
|Tel: +52 55 54 85 34 91|
Fax:+52 55 56 55 10 76