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Novel secretion systems of Mycobacterium tuberculosis and their role in host-pathogen interaction

Objective

Tuberculosis is a major public health threat to the populations of Europe and the world. Mycobacterium tuberculosis, the etiological agent of the disease, can multiply and persist within phagocytic cells and this early event is of primary importance for the outcome of the infection. The main objectives of this proposal are to use highly innovative approaches in molecular and cell biology, biochemistry, immunology and imagery to elucidate the function and interplay of three families of immunogenic proteins of M. tuberculosis, the ESX, PE and PPE families. It was recently found that the ESX systems constitute novel secretion machineries that export major virulence factors and important diagnostic and protective antigens. While the ESX-1 system is responsible for the secretion of the prototypic ESX proteins, namely, the 6 kDa early secreted antigenic target (ESAT-6) and the 10 kDa culture filtrate protein (CFP-10), which are the most important proteins of M. tuberculosis involved in host-pathogen interaction, ESX-5 is implicated in the secretion of PE/PPE proteins. Restriction to pathogenic mycobacteria makes them highly interesting targets for host-pathogen interaction. The ESX-3 system appears to be essential. Thus, in this project we propose to --> analyse the global gene expression network of ESX-1, ESX-3 and ESX-5, --> determine the nature and diversity of the effector proteins they secrete, --> establish their mode of action and sub-cellular localisation, --> survey potential genetic variation in clinical isolates, --> assess their interaction with the immune system of the host, --> evaluate the suitability of ESX systems as drug targets, --> screen small molecules for their potential to inhibit ESX-mediated secretion. The proposed approach will generate major insights into the role of these proteins in pathogenicity that are of utmost importance for the development of new diagnostics, vaccines and therapeutic agents for tuberculosis prevention and control.

Field of science

  • /natural sciences/biological sciences/cell biology
  • /medical and health sciences/health sciences/public and environmental health/epidemics prevention
  • /medical and health sciences/health sciences/public and environmental health
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/basic medicine/immunology
  • /medical and health sciences/clinical medicine/pneumology/tuberculosis

Call for proposal

FP7-HEALTH-2007-A
See other projects for this call

Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

INSTITUT PASTEUR
Address
Rue Du Docteur Roux 25-28
75724 Paris Cedex 15
France
Activity type
Research Organisations
EU contribution
€ 673 040
Administrative Contact
Nadia Khelef (Dr.)

Participants (7)

VRIJE UNIVERSITEIT MEDISCH CENTRUM
Netherlands
EU contribution
€ 361 320
Address
De Boelelaan 1117
1007 MB Amsterdam
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Sylvia Tromp (Ms.)
UNIVERSITA DI PISA
Italy
EU contribution
€ 343 280
Address
Lungarno Pacinotti 43/44
56126 Pisa
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gaetano Privitera (Prof.)
UNIVERSITA CATTOLICA DEL SACRO CUORE
Italy
EU contribution
€ 238 474
Address
Largo Gemelli 1
20123 Milano
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Filippo Leone (Mr.)
ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Switzerland
EU contribution
€ 439 520
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Iain Old (Dr.)
SOUTH AFRICAN MEDICAL RESEARCH COUNCIL
South Africa
EU contribution
€ 218 400
Address
Francie Van Zijl Drive - Parowvalley
7505 Tygerberg
Activity type
Research Organisations
Administrative Contact
Philip Du Plessis (Mr.)
UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Ireland
EU contribution
€ 335 760
Address
Belfield
4 Dublin
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Donal Doolan (Mr.)
UNIVERSITA DEGLI STUDI DI PADOVA
Italy
EU contribution
€ 211 932
Address
Via 8 Febbraio 2
35122 Padova
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Giorgio Bressan (Prof.)