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Immuno VacTB
Tuberculosis
Framework programme: 6
Call: 4
Project number: LSHP-CT-2006-037388
EC contribution: € 857,298
Duration: 24 months
Type: STREP
Starting date: January 2007
Graphic element A new approach for developing a less Immunosuppressive Vaccine for Tuberculosis
Keywords: Tuberculosis; infectious disease; BCG, vaccine; mycobacterial glycolipids

Summary:

Infections due to Mycobacterium tuberculosis cause over 2 million deaths every year. A major problem in combating tuberculosis is the insufficient efficacy of the current vaccine, M. bovis BCG. This is due to the fact that BCG induces, apart from protective Th1 cytokines Il-12 and IFNγ, also the Th2 cytokine IL-4 and the immunosuppressive cytokine IL-10. Together, this response results in subversion of an adequate protective immunity. Current data suggest that two mycobacterial glycolipids, lipoarabinomannan (LAM) and phenolic glycolipid (PGL) play an important role in this immunosuppression. For LAM it has been proposed that especially the terminal mannose residues, the mannose cap, are responsible for its immunosuppressive activity.

A new strategy to overcome these known problems of inefficacy will be followed, and less immunosuppressive BCG strains will be designed, lacking PGL and/or (parts of) the mannose cap. In addition, these novel BCG strains will be an interesting platform to introduce M. tuberculosis genes encoding important antigens, or non-mycobacterial genes that enhance an immunoprotective response.

A prerequisite for the production of this novel M. bovis BCG strain is that the genes involved in the biosynthesis of PGL and the LAM mannose cap are identified. A key gene in PGL biosynthesis (pks15/1) has already been described in literature. The mannosyltransferase responsible for cap synthesis has been recently identified in Mycobacterium marinum by the group of Dr.Appelmelk. A homologue of this mannosyltransferase, designated CapA, is also found in M. bovis BCG and M. tuberculosis. Aim of the project is to isolate BCG strains that lack the LAM mannose cap (or parts thereof). This will be done both in BCG with an intact as well as with an interrupted pks15/1 gene. These recombinant single or double mutant BCG strains will be evaluated in vitro and in vivo for their ability to induce cytokine production and to protect against tuberculosis in a murine infection model.

Background:

The WHO estimates that tuberculosis (TB) kills 2 million people each year and is therefore, after HIV, the second infectious killer worldwide. The currently used vaccine M. bovis BCG (Bacille de Calmette et Guerin), is not sufficiently effective, in particular not against pulmonary TB in adults. One reason for the inefficacy of the vaccine is the ability of BCG to suppress the host immune response. Two immunosuppressive glycolipids, phenolic glycolipid (PGL) and mannose-capped lipoarabinomannan (LAM) have been identified.

The mission of the consortium is "To gain new and improved insights in how the immune system is manipulated by mycobacterial glycolipids with the aim of developing an improved M. bovis BCG vaccine". In pursuit of this mission the consortium will focus on an innovative approach to develop a better BCG vaccine. The following project objective will be pursued in the two year STREP: To construct novel BCG strains that lack (part of) the mannose cap of lipoarabinomanan and/or cannot produce phenolic glycolipid. The combined and coordinated effort of the partners in this project will lead to tangible scientific and technologic advances. To realize this overall project objective, the following scientific and technological objectives will be pursued:

  1. Constructing BCG mutants that cannot synthesize (part of) the mannose cap of lipoarabinomannan (LAM) and/or phenolic glycolipid (PGL)
  2. Determine the structure of LAM and PGL in the mutants
  3. Determine the effects of the mutations on cytokine production by human DCs and T-cells as well as murine macrophages in vitro; the same experiments will be done with purified LAM 4. Determine the effect of the mutations on protection against murine tuberculosis in vivo
  • The results will be published in scientific journals and presented at an international Conference.

Aim:

Less immunosuppressive BCG strains that lack PGL and/or (parts of) the mannose cap will be designed. In addition, these novel BCG strains will be an interesting platform to introduce M. tuberculosis genes encoding important antigens, or non-mycobacterial genes that enhance an immunoprotective response.

Expected results:

To realize the overall project objective, the following scientific and technological objectives will be pursued:

  1. Constructing BCG mutants that cannot synthesize (part of) the mannose cap of lipoarabinomannan (LAM) and/or phenolic glycolipid (PGL).
  2. Determine the structure of LAM and PGL in the mutants.
  3. Determine the effects of the mutations on cytokine production by human. DCs and T-cells as well as murine macrophages in vitro; the same experiments will be done with purified LAM.
  4. Determine the effect of the mutations on protection against murine tuberculosis in vivo.

Potential applications:

The project will lead to an increased understanding of the pathogenesis of the TB bacterium and its interaction with the immune system. If the mutations predicted to lead to a better vaccine indeed have this effect, a follow up project will be started to develop an improved vaccine.

Coordinator:

Bernard A.M. van der Zeijst, Ph. D.,
Scientific Director,
Netherlands Vaccine Institute,
3720 AL Bilthoven,
The Netherlands
Tel: +31-30-274-4164
Fax: +31-30-274-4439
E-mail: ben.van.der.zeijst@nvi-vaccin.nl
Website: www.nvi-vaccin.nl

Partners:

Principal
Scientific
Participants
Official Address Other Information
2 B.J. Appelmelk Dept. Med. Microbiology
VUmc Vrije Universiteit Med. Center
van der Boechorststraat 7
1081 BT Amsterdam
The Netherlands
Tel: +31 20 4448297
Fax: + 31 20 4448318
E-mail: bj.appelmelk@vumc.nl

3 Rui Appelberg, Institute for Molecular and Cell Biology
Rua do Campo Alegre 823
4150-180 Porto
Portugal
Tel: +351.226074952
Fax: +351.226099157
E-mail: rappelb@ibmc.up.pt
Website: http://www.ibmc.up.pt/
4 Germain Puzo

Laboratoire "Immunochimie
et Glycoconjugués Mycobactériens"
Département des mécanismes
moléculaires des infections
mycobactériennes
Institut de Pharmacologie et Biologie Structurale
205, route de Narbonne
31077 Toulouse
France

Tel: 33 (0)5 61 17 55 04
Fax: 33 (0)5 61 17 55 05
E-mail: germain.puzo@ipbs.fr
Website: http://www.ipbs.fr

 
 
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