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Immuno VacTB


Tuberculosis

A new approach for developing a less Immunosuppressive Vaccine for 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

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 IFN?, 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.

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