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MM-TB
TUBERCULOSIS
Framework programme: 6
Call: 2
Project number:
LSHP-CT-2004-012187
EC contribution: € 976,000
Duration: 24 months
Type: STREP
Starting date: 1 January 2005
Graphic element Molecular Markers of M. tuberculosis Early Interactions with Host Phagocytes
Keywords: Immunology; vaccines; tuberculosis; mycobacteria; dendritic cells; macrophages; microarray; transcriptional profiling; database; vaccine

Summary:

Comparative genomics offers a highly innovative opportunity to decipher M. tuberculosis interactions with the immune system, using transcriptional profiling approaches. In particular, early interactions between M.tuberculosis and host phagocytes, namely macrophages and dendritic cells (DC), are thought to play a crucial role in mounting a protective immune response, and in determining the outcome of infection. Microarrays will be used to study simultaneously the entire expressed genomes of both the mammalian host and the microbial parasite during their interaction. Data analysis of the M. tuberculosis arrays, developed by the participants, will reveal patterns of the induced gene expression and, most likely, unique novel targets for vaccine design. Data analysis of mouse and human arrays (GeneChips by Affymetrix) of M.tuberculosis-infected monocytes and dendritic cells will allow identification of molecular markers and pathways associated with protection.
This STREP fully integrates the activities of internationally recognised groups that have pioneered the TB field and the development of M.tuberculosis arrays with groups that have developed immuno-genomics and, in particular, transcriptional profiling analysis of phagocytic cells. These groups will implement an IT-based integrated knowledge management system providing a new centralised European resource - a transcriptional TB databases. This transcriptional profiling database should have a major impact on the identification of new molecular markers and molecular targets, and will certainly support the recent European TB vaccine effort.

Background:

Tuberculosis is a major public health problem. One third of the world population is estimated to carry latent infections, and active disease kills nearly 1.5 million individuals every year. The global incidence of TB increases by 2% annually. An additional major problem is the increasing incidence of multi-drug resistances (MDR) in Eastern Europe. More than 14% of primary TB infections are MDR cases in several Eastern European countries. The future development of a new vaccine against TB demands a better understanding of the interactions between M.tuberculosis and the immune system of its host, as well as the identification of markers of protection against TB for an appropriate and informative follow-up on individuals included in phaseI/II vaccine trials.

In particular, early interactions between the tubercle bacillus and host phagocytes, namely macrophages and dendritic cells, are thought to play a crucial role in mounting a protective immune response, and in determining the outcome of infection (1). These antigen-presenting cells are the very first cells encountered by the bacillus during a natural infection. They present mycobacterial antigens to T lymphocytes and shape the type of immune response by secreting cytokines. Identification of signals induced by these DC and the other interacting cell populations should help to design markers of protection.

Aim:

The goal of this project is to develop and design new markers of protection and to identify unique molecular patterns both in the microbe and in the host cells, associated with early interactions between M.tuberculosis and phagocytic cells.

Expected results:

We should be able to define global molecular patterns associated with protection and identify novel microbial antigens or pathways that may be targeted by future chemotherapy and vaccines.

The partners will implement an IT-based integrated knowledge management system providing a new centralised European resource - a transcriptional TB database.

Potential applications:

This transcriptional profiling database should have a major impact on the identification of new molecular markers and molecular targets, and will certainly support the recent European TB vaccine effort, specifically by enabling us to define the sub-populations to be included in future vaccine trials better.

Coordinator:

Paola Ricciardi-Castagnoli
Department of Biotechnology and Bioscience
University of Milan-Bicocca
P.zza della Scienza 2
20126 Milan
Italy
Tel: +39 02 6448 3559
Fax: +39 02 6448 3552
E-mail: Paola.Castagnoli@unimib.it
Website: http://www.btbs.unimib.it

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Olivier NeyrollesCNRS (URA 2172)
Institut Pasteur
Unité de Génétique Mycobactérienne
28 rue du Roux
FR-75015 Paris
France
Tel: +33 1 45 68 88 40
Fax: +33 1 45 68 88 43
E-mail: neyrolle@pasteur.fr
Website: http://www.pasteur.fr
3Neil StokerProfessor of Molecular Bacteriology
Department of Pathology and Infectious Diseases
Royal Veterinary College
Royal College Street
UK-NW1 0TU London
United Kingdom
Tel: +44 20 7468 5272
Fax: +44 20 7468 5306
E-mail: nstoker@rvc.ac.uk
Website: http://www.rvc.ac.uk/
4Philip D Butcher
Professor of Molecular Medical Microbiology
Dept. Cellular & Molecular Medicine (Medical Microbiology)
St George’s Hospital Medical School
UK-SW17 ORE London
United Kingdom
Tel: +44 20 8725 5721
Fax: +44 20 8672 0234
E-mail: butcherp@sghms.ac.uk
Website: http://www.sghms.ac.uk
5Filippo PetraliaSekmed S.R.L.
Corso Magenta 31
IT-20123 Milan
Italy
Tel: +39 340 233 7275
Fax: +39 028 621 30
E-mail: sekmed@virgilio.it
Website: http://www.sekmed.com

 
 
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